This was a planned secondary analysis of the clinical and cost data collected from the CLIP cRCTs (NCT01911494) in India, Pakistan and Mozambique (13), based on a previously published protocol (14) and reported in line with a CHEERS checklist (15). (See Supplementary Appendix 1 for the Statistical Analysis Plan [SAP]).
Study population:
The CLIP trials targeted pregnant women (15-49 years in India and Pakistan, and 12-49 years in Mozambique) across all intervention and control clusters (12 in each of India and Mozambique, and 20 in Pakistan). All women enrolled provided written consent. All were included in the economic analysis provided they had delivered by trial end and had data on the primary outcome of a composite of maternal and perinatal morbidity or mortality.
CLIP Intervention:
The methods for the CLIP trials are described in detail elsewhere . Briefly, each of the cRCTs aimed to reduce all-cause maternal and perinatal morbidity and mortality by community-level initial triage and treatment of hypertensive women in their community, and timely transfer to facility. The intervention combined community engagement and pregnancy hypertension-focussed home contacts by CHWs (i.e., accredited social health activists and auxillary nurse midwives (India), lady health workers (Pakistan), and agentes polivalentes elementares (Mozambique)). Community engagement meetings focussed on pre-eclampsia awareness and education around birth preparedness and complication readiness, and included the pregnant women themselves, as well as their family members and community stakeholders. CHW-led home contacts were centred around the use of the PIERS (Pre-eclampsia Integrated Estimate of RiSk)-On-the-Move (POM) mobile health application for risk stratification (16). The POM application helped CHWs to respond to emergency conditions, take women’s blood pressures, assess proteinuria (using dipsticks, at the first and any subsequently hypertensive visit), and use pulse oximetry (in Pakistan and Mozambique). For hypertensive women, the POM application directed CHWs to administer oral methyldopa, intramuscular magnesium sulphate, or refer to a comprehensive emergency obstetric care facility depending on the particular circumstance. In the control group, women received routine antenatal and postnatal care. In both control and intervention arms, relevant demographic, care-seeking, and clinical data were obtained at enrolment, through to 28 days postpartum (newborn) and six weeks (mother), through regular cross-sectional household surveys (every 3-6 months) and, in India, with additional facility record review.
Costs:
Within each country, detailed costs associated with the intervention were collected from annual budgets, receipts, and the number of intervention-related activities performed. Costs were divided into five main categories: 1) CHW training, 2) health worker incentives for providing POM visits, 3) drug administration costs resulting from POM visits, 4) community engagement sessions, and 5) supplies; for details, see Table S2. Total cost of the intervention is the sum of these five categories. Discounting of costs was not necessary due to the relatively short time period of the analysis. In the main analyses, we did not account for potential costs associated with differences in care-seeking (antenatally or postnatally) between intervention and control, as these measures were broadly similar between arms (8–10). In Pakistan, we included out-of-pocket costs to women, gathered by pilot tested focus-group discussions, in a separate analysis (Table S2). We did not account for the cost of trial surveillance in both arms, as a potential scale-up of this intervention would not incur these costs. Costs for each country were converted into USD rates based on the average exchange rate during the trial (i.e., India: 1 USD = 60 INR, Pakistan: 1 USD = 104.7 PKR, and Mozambique: 1 USD = 64.67 MZN).
Outcomes
The primary clinical endpoint was mortality for mothers and infants, including stillbirth and neonatal death. These rates were translated into years-of-life-lost (YLL) based on country-specific World Health Organization (WHO) life expectancies (17). In contrast to the CLIP primary composite outcome, pregnancy-related morbidities for mothers and newborns were not included, as there are no validated years-of-life-disabled or disabilities associated with many of these outcomes in any of the three countries (18). Cost-effectiveness was summarised by incremental cost-effectiveness ratios (ICERs), which are interpreted as the average incremental cost relative to one year of life saved. That is, the cost that a policy maker would have to pay to extend life by one year.
Study perspective:
The cost-effectiveness analyses were based on a programmatic perspective, comparing the incremental cost of implementing the intervention both overall, and for various scenarios of POM-guided contacts delivered. This comparison assessed the cost to the health system of implementing the CLIP intervention at various levels but did not account for potential additional costs to women and their families, other than in a secondary analysis in Pakistan.
Data analyses:
The primary economic model used for the base case analysis and probabilistic sensitivity analysis was a decision-tree (19) based on the following possible decision points: i) arm of the trial; ii) number of POM contacts grouped into one of 0, 1-3, 4-7, or ≥8 (within intervention arm branch); iii) whether or not a POM-guided contact resulted in a referral to facility or use of either methyldopa or magnesium sulphate; and iv) outcome of pregnancy: maternal death, stillbirth, neonatal death or survival. See Figure S1 for details.
Within each country, the probability of each of these branches was estimated directly from the CLIP trial surveillance and POM databases. Standard errors for these probabilities were estimated and adjusted for the clustered structure of the data, and associated mean costs were estimated for each branch. Community engagement costs were assumed to be distributed evenly across the varying POM contact frequency groups. All other costs (CHW training and incentives, supplies, drugs) were distributed on a per contact basis, meaning branches on the tree corresponded to groups with more POM-guided contacts and associated costs, to appropriately estimate the associated implementation cost of each frequency (‘scenario’) of the intervention.
We conducted a standard probabilistic sensitivity analysis (20) to determine the uncertainty associated with our analyses. For this, probability and costs for each branch were simulated using the above parameters. Costs were assumed to have gamma distributions, outcomes were assumed to have beta distributions, and the probability of each number of POM visits was drawn from a Dirichlet distribution (Table S3). These simulations were run 10,000 times for each country and the results summarised with 95% credible intervals (as the 2.5th and 97.5th percentiles of the 10,000 runs) for the YLL, cost, and ICERs for each trial arm as well as at each intervention scenario. Results were also visualised using a cost-effectiveness plane (with points in the top, right corner considered to be cost-effective), and with willingness to pay curves and thresholds for each YLL averted (which shows for increasing cost to a decision maker the likelihood the intervention is cost-effective). Willingness to pay thresholds were based on three times the country-specific GDP/capita in 2016 (India = $5188, Mozambique = $1287, Pakistan = $4105).
All analyses were carried out using R Version 3.5.3.