Optimizing treatment for the prevention of pre-eclampsia/eclampsia in Nepal: is calcium supplementation during pregnancy cost-effective?
© The Author(s) 2016
Received: 19 February 2016
Accepted: 2 December 2016
Published: 28 December 2016
In Nepal, pre-eclampsia/eclampsia (PE/E) causes an estimated 21% of maternal deaths annually and contributes to adverse neonatal birth outcomes. Calcium supplementation has been shown to reduce the risk of PE/E for pregnant women and preterm birth. This study presents findings from a cost-effectiveness analysis of a pilot project, which provided calcium supplementation through the public sector to pregnant women during antenatal care for PE/E prevention as compared to existing PE/E management in Nepal.
Economic costs were assessed from program and societal perspectives for the May 2012 to August 2013 analytic time horizon, drawing from implementing partner financial records and the literature. Effects were calculated as disability-adjusted life years (DALYs) averted for mothers and newborns. A decision tree was used to model the cost-effectiveness of three strategies delivered through the public sector: (i) calcium supplementation in addition to the existing standard of care (MgSO4); (ii) standard of care, and (iii) no treatment. Uncertainty was assessed using one-way and probabilistic sensitivity analyses in TreeAge Pro.
The costs to start-up calcium introduction in addition to MgSO4 were $44,804, while the costs to support ongoing program implementation were $72,852. Collectively, these values correspond to a program cost per person per year of $0.44. The calcium program corresponded to a societal cost per DALY averted of $25.33 ($25.22–29.50) when compared against MgSO4 treatment. Primary cost drivers included rate for facility delivery, costs associated with hospitalization, and the probability of developing PE/E. The addition of calcium to the standard of care corresponds to slight increases in effect and cost, and has a 84% probability of cost-effectiveness above a WTP threshold of $40 USD when compared to the standard of care alone.
Calcium supplementation for pregnant mothers for prevention of PE/E provided with MgSO4 for treatment holds promise for the cost-effective reduction of maternal and neonatal morbidity and mortality associated with PE/E. The findings of this study compare favorably with other low-cost, high priority interventions recommended for South Asia. Additional research is recommended to improve the rigor of evidence available on the treatment strategies and health outcomes.
KeywordsPre-eclampsia Eclampsia Maternal mortality Nepal Low-income countries Antenatal care Calcium Micronutrients Magnesium sulfate Cost-effectiveness
Maternal and neonatal morbidity and mortality due to preventable causes contribute to a staggering proportion of the world’s burden of disease. In 2013, an estimated 289,000 women died from complications associated with pregnancy or childbirth; 27.1% due to hemorrhage, 14.0% hypertensive disorders, and 10.7% sepsis between 2003 and 2009 [1, 2]. Among children under five, 45% of deaths in 2015 occurred within the first 28 days of life with 28% of deaths due to pre-term causes [3–5]. In Nepal, an estimated 1500 maternal and 12,000 neonatal deaths occurred in 2015 [6, 7]. The country has seen reductions in maternal and under-five mortality by 76% and 71%, respectively, since 1990 [7, 8]. However, maternal deaths still make up nearly 10% of deaths among women of reproductive age and surveys show that the reduction in neonatal mortality, at only 34% in Nepal, greatly lags behind achievements in under-five and infant mortality [5, 8].
Eclampsia is the leading direct cause of maternal mortality in Nepal, occurring in 1 in 25 women and resulting in an estimated 21% of maternal deaths annually [9, 10]. The condition is also associated with adverse neonatal outcomes, including higher rates of neonatal intensive care unit admission and length of stay, small for gestational age, stillbirth, and mortality [11–15]. Because termination of pregnancy is the definitive management of gestational hypertension and eclampsia, such complications remain the leading cause of provider-initiated preterm delivery globally [16, 17]. Magnesium sulfate (MgSO4) may significantly reduce the risk of recurring seizures to as low as 19%, and is used regularly across Nepal [10, 18–23]. In some cases, cesarean sections are performed to ensure the safety of both mother and child . Efforts toward the prevention of pre-eclampsia/eclampsia (PE/E) may contribute to reductions in maternal and perinatal mortality. In multiple clinical trials, low-dose calcium supplementation has been shown to reduce the risk of PE/E for pregnant women and preterm birth [14, 15, 22, 25, 26]. The World Health Organization (WHO) currently recommends that 1.5–2.0 g of calcium be taken daily during pregnancy for the prevention of PE/E, beginning at a gestational age of approximately 20 weeks .
Screening and early identification of women at risk for PE/E may enable appropriate antenatal care (ANC), management, and treatment. Evidence from high resource settings on the cost-effectiveness of PE/E screening is favorable [28, 29]. Findings from 33 countries included in the Magnesium Sulphate for Prevention of Eclampsia (Magpie) Trial suggest that prophylactic treatment of PE/E with MgSO4 is cost-effective for severe cases and when magnesium sulfate is available at little to no cost . Analysis of prophylaxis strategies in the United States determined that universal prophylaxis with MgSO4 for all women with pre-eclampsia is cost-effective compared with treating only those with severe disease . Meta-analyses assessing the cost-effectiveness of testing and treatment options for PE/E from the perspective of the United Kingdom’s National Health System suggest that providing calcium to all women without initial screening for PE/E is the most effective “test/treatment” option [29, 32]. However, the existing literature fails to conclusively determine whether calcium supplementation interventions are cost-effective in low-income settings.
From May 2012 through August 2013, the Ministry of Health and Population (MOHP) in Nepal, with technical support from the USAID-funded Maternal and Child Health Integrated Program (MCHIP) and Jhpiego, implemented a pilot program testing the feasibility of providing calcium supplements to pregnant women to prevent PE/E. The objective of the overarching study was to evaluate this pilot program and generate evidence informing future decisions for scale up. The primary aim of this model-based sub-study is to determine the incremental cost-effectiveness of calcium supplementation for PE/E prevention as compared to existing curative PE/E management in Nepal. Secondary objectives sought to explore the incremental cost effectiveness of three alternatives: (i) calcium supplementation in addition to MgSO4 (i.e. the existing standard of care), (ii) the existing standard of care, and (iii) no treatment for PE/E.
Ethical approval was obtained from Nepal Health Research Council and the Johns Hopkins University Bloomberg School of Public Health institutional review board.
Study setting and context
This pilot program was implemented in Dailekh District in the Mid-Western Region of Nepal based on the recommendations of a Technical Advisory Group formed to guide program implementation. Dailekh District, 650 km from Kathmandu, covers 1505 km2 with elevation ranges from 544 to 4168 m above sea level . This mountainous district was chosen because its terrain represents the most common type of district in Nepal while having a greater population. As a result, it may most accurately illustrate the challenges associated with implementation nationwide. Dailekh had an estimated population of 264,616 in 2011, 51% of whom are women [33, 34].
The District Health Office provides preventive, curative, and promotional health services through 60 Health Facilities (HFs) . Over 800 female community health volunteers (FCHVs) promote maternal and child health services across the district, corresponding to 1 FCHV per 1000 population. Utilization rates for key reproductive, maternal, newborn and child health services exceed national level estimates for most critical indicators. During pregnancy, 29% of women report receiving no ANC services at all compared to a national rate of 15.2% [33, 35]. Similar trends are reported for delivery careseeking with 59% of women delivering with the assistance of a skilled birth attendant, compared to 36% of women nationally [33, 35].
Project activities began in May 2012 and spanned through August 2013. Startup activities included the development of training manuals on calcium supplementation, behavior change communication (BCC) materials, monitoring and evaluation tools, and initiation of training activities. Monitoring and evaluation tools were developed in line with the existing health management information system tools (i.e. calcium registers for ANC providers, calcium information added to existing FCHV registers, and reporting forms for village health workers and facility-level health providers). The supply of calcium supplements was purchased from Missionpharma India in 2012 and from Curex Pharmaceuticals Nepal in 2013.
To initiate district level activities, a half-day orientation was held for district level stakeholders. Four one-day training of district-level trainers with 95 attendees total followed. Sixty-one-day trainings at the health facility level trained all 268 ANC health workers in the district, while another 60 one-day trainings trained all 810 FCHVs. A full calcium supply and logistics support was provided to all health facilities. ANC health workers at government health facilities were trained to counsel pregnant women on the benefits of calcium supplementation during pregnancy and to distribute calcium during ANC visits. Health workers were also trained in the use of magnesium sulfate for treatment of severe PE/E and to perform PE/E screening using blood pressure measurements and urine protein tests, conducted upon each ANC visit. Health facilities were provided with urine collection bottles and dipsticks to ensure the availability of PE/E screening services for pregnant women during ANC visits. FCHVs were trained to promote ANC attendance and compliance with the recommended calcium regimen. Pregnant women attending an ANC visit were given a calcium supply for the remainder of their pregnancy. Women were typically provided with 300 calcium tablets if enrolled at ≤5 months gestational age and 100–200 tablets if enrolled at later gestational age. The recommended calcium intake was 1 g daily (2 tablets of 500 mg each), beginning at 16 weeks gestational age until delivery.
The national standard drug for treatment of severe PE/E in Nepal is MgSO4, administered by health facility providers following screening for PE/E . Program activities sought to expand the existing standard of care to include the provision of calcium supplements (i.e. MgSO4 + Calcium). In this analysis, we compare the costs and effects of the (i) MOHP calcium supplementation program in addition to the standard of care (i.e. MgSO4 + Calcium) against two hypothetical arms, (ii) MgSO4 treatment alone (i.e. standard of care in Nepal) and (iii) no treatment.
Total costs and inputs in 2014 USD
Distribution for PSA
Total fixed program costs
Blood pressure instrument
Total (not incl. variable costs, listed below)
Total program costs (per individual)
Variable costs per individual
Urine test (sample bottle + dipstick)
Calcium supply (per bottle, 100 tablets)
MgSO4 treatment regimen
Mean daily bed fee for maternal hospitalization
Other maternal hospitalization costs
Mean daily bed fee for newborn hospitalization
Other newborn hospitalization costs
Mean indirect costs per individual
Daily wage in district
Round trip transportation for hospitalization
Mean duration of hospital stay
Normal, healthy case
Background epidemiological and program data
Distribution for PSA
ANC, at least one visit
Facility deliveries in government sector
Incidence of eclampsia
Eclampsia as direct maternal cause of death
Mean age of eclampsia patients
MgSO4 for PE/E management
Maternal risk ratios for PE/E
MgSO4, standard regimen
Still birth rates
Vaginal birth among PE/E cases
Cesarean delivery among PE/E cases
Disability-adjusted life years (DALYs)
DALYs averted per individual (maternal)
DALYs averted per individual (newborn)
Pilot Program Data, Dailekh District, 2013
ANC, at least one visit
Calcium regimen compliance
Partial or low compliance
Gestational age among women receiving calcium
4–5 months (300 calcium tablets)
6–7 months (200 calcium tablets)
8–9 months (100 calcium tablets)
The efficacy of MgSO4 treatment and cesarean section indicated as risk ratios were applied to outcomes accordingly. Those with partial or low compliance with the full calcium regimen (300 tablets) were conservatively assumed to experience no effects of calcium supplementation in the prevention of PE/E. Because the relevant mortality risk data were unspecified, it was assumed that the probability of maternal and newborn death was similar for at-home and facility deliveries. The average age of a maternal death was 23.4 years based on the mean age of eclampsia patients in Nepal, and the life expectancy for females in Nepal was 69 years of age [38, 39]. Newborn YLLs were determined using the mean life expectancy of males and females in Nepal, which is 68 years of age . To generate years lost to disability (YLDs), disability weights for hypertensive disorders of pregnancy (0.00)  were used for mothers. The average age of onset used in the calculation of newborn YLDs was 0.0 years because mortality rates used in the model were associated with stillbirth.
Base case DALYs for mothers and newborns were discounted at a rate of 3% without age weighting. Incremental DALYs averted through the calcium supplementation program were calculated separately for mothers and newborns using relevant parameters, and summed for each study arm to generate a summary estimate of DALYs for each arm.
Comparisons of costs and effects for each study arm were used to generate incremental cost effectiveness ratios (ICERs). Variations in individual parameters were tested within this framework using one-way and multi-way sensitivity analyses. The probabilities of compliance with the calcium regimen, risk ratio for the prevention of PE/E with calcium supplementation, and rates of screening, hospitalization, MgSO4 treatment, and cesarean section were varied. The costs associated with calcium supply, magnesium sulfate treatment, urine tests, and blood pressure testing were highlighted as costs of interest in these analyses as these were key commodities used in implementation of the program. These costs of interest as well as costs related to hospitalization were varied by 25% in sensitivity analyses with the exception of calcium supply, which had an upper bound of $1.42 USD per 100 tablets based on supplier prices (Table 1). Effects were varied from a base case of 3% discounting and no age weighting, to a high value under 3% discounting and age weighting and a low of 6% discounting and age weighting. A tornado diagram was generated to display variations in individual parameters in the univariate sensitivity analysis. Probabilistic sensitivity analyses explored the effect of simultaneous variations in multiple parameters.
Thresholds for determining cost-effectiveness
Overall findings on the cost per DALY averted for each option were evaluated according thresholds established in 2002 by the Commission on Macroeconomic and Health (CMH).1 Findings were additionally contextualized against estimates of the cost per DALY averted for other low cost high priority interventions stipulated by Disease Control Priorities, 2nd ed. and other examples of calcium and MgSO4 programs published in the literature. Cost-effectiveness acceptability curves were generated to approximate the proportion of iterations that were cost-effective for each study arm for willingness-to-pay (WTP) thresholds between $0 and $100 USD.
Summary of total costs and effects by comparator
MgSO4 + calcium
All pregnant women attending at least one ANC visit were provided with a calcium supply corresponding to gestational age. ANC users at 4 or 5 months of pregnancy (82.2%) received 300 tablets, at 6 or 7 months (13.8%) received 200 tablets, and at 8 or 9 months (4.0%) received 100 tablets (Table 2). Of those women receiving calcium supplements, 67.3% reported adherence to the full course. The remaining 32.7% reported either completing a partial course or low compliance with the calcium regimen. Among women in the pilot program, the added probability of getting screened for PE/E risk through blood pressure measurement or urine testing was high (99.94%). The average risk ratio of PE/E with calcium supplementation during pregnancy is 0.45 (95% CI: 0.31, 0.65) . This efficacy was applied in the model only for those women receiving and compliant with the full course (300 tablets) of calcium supplementation.
The proportion of births delivered in government facilities nationally (26%) was used as a proxy measure for the rate of hospitalization in Nepal since these data were not readily available, either nationally or from program data . Among surveyed government hospitals, 68.9% of women received m MgSO4 treatment for severe PE/E management. This value was used to indicate the proportion of women receiving MgSO4 sulfate treatment. The efficacy of MgSO4 in the treatment of PE/E used in the analysis was a risk ratio of 0.19 . The probability of a cesarean section for inpatients of government hospitals was determined by the rate of cesarean sections as a mode of delivery (55.3%) and their availability in government hospitals (71%) [10, 19]. The mortality rate used for pregnant women in the model was specific to eclampsia as a direct cause of maternal death (21%) . Table 3 indicates the total effects associated with each condition considered in the model.
Summary of incremental cost-effectiveness ratios
Total incremental costs
Total incremental DALYs averted
Incremental cost per DALY averted
Total incremental costs
Total incremental DALYs averted
Incremental cost per DALY averted
MgSO 4 a vs.
MgSO4 + calcium vs.
MgSO4 + calcium vs.
MgSO 4 a
Study findings suggest that MgSO4 treatment of PE/E in Nepal is cost-effective when compared to no treatment at all. The addition of calcium supplementation increases costs and corresponds to a minor increase in effectiveness when compared against a scenario of no PE/E management. Despite the low incremental cost-effectiveness ratios across comparisons, findings suggest that for individuals only willing to pay $10 USD or less, MgSO4 is the preferred strategy for preventing PE/E. However, for individuals willing to pay more than $35 USD, calcium in addition to MgSO4 offers the best value for money.
Cost per DALY averted associated with low-cost high-priority interventions recommended for South Asia
Low-cost high-priority interventions recommended for South Asia
Mean cost per DALY averted (USD)
Additional coverage of traditional Expanded Program on Immunization
Full course calcium supplementation (82.2%) with 67.3% compliance in addition to MgSO 4 (68.9%) in Nepal
Voluntary counseling and testing
Peer-based programs targeting at-risk groups
School-based interventions that disseminate information to students
Prevention of mother-to-child-transmission with antiretroviral therapy
Surgical services and emergency care
Surgical ward in a district hospital
Staffed community ambulance
Training of lay first responders and volunteer paramedics
Childhood vaccination against endemic TB
Directly observed short-course chemotherapy
Isoniazid treatment of epidemic TB
Management of drug resistance
Using MgSO4 prophylaxis for only severe cases of pre-eclampsia in low GNI countries
Maternal and neonatal care
Increased primary care coverage
Improved quality of comprehensive emergency obstetric care
Improved overall quality and coverage of care
Neonatal packages targeted to families, communities, and clinics
Incremental cost of preventing one case of eclampsia using MgSO4 in low GNI countries
Beyond efforts to contextualize study findings with alternative programs and resource uses, we considered findings against the gross domestic product (GDP) of Nepal of $697 per capita in 2014 —the threshold value for cost-effectiveness established by WHO CHOosing Interventions that are Cost Effective (WHO-CHOICE) and CMH . The model demonstrates that calcium supplementation in addition to MgSO4 becomes more cost-effective with increased rates of PE/E. This suggests that the intervention would offer the greatest value for money in districts with higher incidence rates of the disease. If calcium supplementation is to be nationally adopted, targeting prevention efforts where incidence of PE/E is particularly high is recommended.
In 2005, the Government of Nepal established the Aama program, or Safe Delivery Incentive Program (SDIP), a demand-side financing scheme providing incentives to women to deliver in health facilities in order to improve mothers’ health outcomes and that of their child. In January 2009, user fees were removed for all types of delivery in government health facilities as well as selected accredited private hospitals. Under the Aama program, cash payments in the amount of NPR 500–1500 ($5.28–15.83 USD) depending on district terrain are made to women to pay for transportation to facilities for delivery . The Aama program also provides incentives to the health facility for deliveries; participating health facilities are reimbursed NPR 1000–1500 ($10.55–15.83 USD) for normal deliveries, NPR 3000 ($31.66 USD) for complicated deliveries, and NPR 7000 ($73.87) for cesarean deliveries . However, our model estimates these costs based on surveys conducted at three government hospitals. Survey findings indicated higher mean costs associated with transportation and hospitalization by type of delivery, thereby providing more conservative estimates of anticipated costs incurred by users and the health system.
The majority of cost-effectiveness drivers are associated with processes tied to hospitalization. Increases in the rates of hospitalization for facility delivery generally resulted in increased costs per DALY averted, suggesting that costs bring about greater impact on cost-effectiveness ratios than the health effects brought about by this intervention. Effectiveness data specific to the nuances of compliance to the calcium regimen and for women of different levels of risk of onset would provide better evidence in this regard.
Hospitalization for facility delivery is directly linked with the probability of receiving MgSO4 treatment and/or undergoing a cesarean section for PE/E. The cost of hospitalization and the additional cost of cesarean section procedures constituted the highest cost values incorporated into the model. As a significant proportion of overall costs, it corresponds that these cost factors have a greater impact on incremental cost-effectiveness ratios when varied. Still, with improved utilization of facilities for delivery, it may be possible to decrease the costs of hospitalization and cesarean section procedures and generate overall better health outcomes with PE/E hospitalization and treatment.
Increased use of calcium supplementation for the prevention of hypertensive disorders of pregnancy in the South Asia region may also result in reductions in the cost of calcium supply, further improving cost-effectiveness. A critical factor in determining whether or not mothers receive calcium supplementation and/or early treatment is ANC utilization. The Government of Nepal introduced the 4ANC incentive program in July 2009, providing cash payments to women NPR 400 upon following the ANC protocol of four ANC visits at specific gestation times, institutional delivery, and a postnatal visit . Further increasing ANC and early ANC may serve to further increase use of and adherence to calcium. The combination of these efforts for the prevention of PE/E may culminate into a synergistic effect for optimal cost-effectiveness for Nepal and similar settings.
This analysis was carried out retrospectively as part of the evaluation of a small-scale pilot program in the Dailekh District of Nepal. In the absence of a comparison area, the program is compared against hypothetical comparators of no calcium distribution to women during ANC. As extended observation of person-time spent administering calcium supplementation and counseling was not conducted as part of this pilot program evaluation, the time of health care providers to administer and counsel patients has not been included in this analysis. In the model, utilization of MgSO4 and cesarean delivery as a treatment for PE/E and their respective effects remained the same across arms regardless of case severity. Severity can also have considerable implications for morbidity and mortality that affect results. Differences in PE/E management according to case severity were not modeled because limited data exists describing differentiated effects for mothers and newborns based on PE/E severity.
We note that women attending at least one ANC visit may have a greater rate of hospitalization for various reasons. It is also possible that there is a greater hospitalization rate and treatment measures provided for mothers experiencing more severe PE/E. These nuances are not captured in the model due to lack of differentiated data. Beyond these parameters, the model relies upon secondary data to address gaps in primary data on mortality and many of the provider and users’ cost categories. Primary data on reported compliance with calcium regimens provided were drawn from household survey data provided by the program and may be vulnerable to recall bias.
Calcium supplementation for pregnant mothers provided with appropriate MgSO4 treatment holds promise for the cost-effective reduction of maternal and neonatal morbidity and mortality associated with PE/E. As modeled by the MOHP calcium supplementation pilot program in Nepal, such calcium interventions may be similarly cost-effective in other low-income settings. Additional research is recommended to further explore the implications of calcium on newborn outcomes and delivery at scale. Future research is needed to understand factors that may improve early initiation of ANC and increase rates of facility delivery. Efforts to deliver calcium at scale offer the potential to yield even greater cost-effectiveness given the high utilization of ANC—the delivery point of calcium supplementation.
The CMH stipulated that an intervention is highly cost effective (HCE) if it has a cost per DALY averted which is lower than the Gross Domestic Product (GDP) per capita. Interventions with a cost per DALY averted of less than 3 times the GDP per capita are deemed cost effective, while those with a DALY averted which is 3 times that of the GDP are considered cost ineffective. Considering costs according to these standardized thresholds will help to facilitate the interpretation of findings by decision-makers.
behavior change communication
Commission on Macroeconomic and Health
disability-adjusted life year
Female Community Health Volunteers
gross national income
incremental cost-effectiveness ratio
Maternal and Child Health Integrated Program
- MgSO4 :
Ministry of Health and Population
Technical Advisory Group
United States dollar
World Health Organization
years lost to disability
years of life lost
KT, DR, JB, BR, PC and CR conceived study concept and collected data for model inputs. AEL and IF designed the model and conducted subsequent analyses. IF gathered additional data from secondary sources necessary for model assumptions. IF wrote the first draft with AEL and provided revisions of the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
This work was supported by the U.S. Agency for International Development (USAID). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit for publication.
This study was made possible by the generous support of the American people through USAID. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID.
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