Written informed consent was sought from all individuals who participated in the ANC exit survey and the questionnaire to the health workers, before conducting any study procedures. All study protocols and informed consents were approved by the Ethics Committee of the Hospital Clinic in Barcelona, the WHO ethics review board [(ERC.0003384 – 02/10/2020; (CCI/051/AGO/2020 – 20/08/2020)]

This costing study was part of a multi-country project to assess the effectiveness and cost-effectiveness of community-based delivery of intermittent preventive treatment (C-IPTp) of malaria during pregnancy ¹¹ . The study was conducted in 12 rural districts in four SSA countries: DRC, MDG, MOZ and NGA. The selection of these countries was based on criteria that included the existence of an operative system of community health workers (CHW), having IPTp policies in place, commitment from the Ministry of Health (MoH) and high malaria endemicity. The study areas were heterogeneous in terms of the demographic and health profiles, but all them were endemic of malaria, with the disease being among the leading causes of maternal and child mortality ¹¹ . Further details on the study setting have been published elsewhere ^{12, 13} .

The economic costs of malaria in pregnancy include the cost to the health system that provides prevention and treatment services, and the cost to households who access these services.

To collect the household costs of malaria in pregnancy, we administered an exit survey questionnaire to pregnant women when leaving a routine ANC visit from October 2020 to June 2021. As such, only women of reproductive age, being pregnant and after leaving a routine ANC visit were selected to participate. Sample size for the minimum number of pregnant women to be interviewed was calculated as follows: n ≥ Z _α^2 (p(1-p))/e^2, where Z is the critical value of the normal distribution at level α=0.05 (95% confidence level), e is the margin of error ( e=0.05) and p is the households cost variability ¹³ . Minimum sample size, assuming a 10% of dropout rate, resulted in 426 pregnant women interviewed per country.

To estimate the health system costs associated to control of MiP, interviews were administered to health workers (1 per health facility) from a random sample of 30% of the existent facilities within the district. This resulted in a total of 133 health workers from 133 different health facilities being approached and interviewed, with any participant declining or withdrawing later on from the interview (see Table S1 ¹⁴ ).

All women leaving an ANC visit were approached for an interview. For those women that met the inclusion criteria, (i.e., being pregnant, living in the study area and leaving an ANC consultation), we sought written consent to participate. Participants were asked about the direct and indirect costs associated to attending a routine ANC visit, where malaria prevention services are provided. Direct costs (out-of-pocket expenses) were broken into medical (e.g., drugs and tests, registration fees), and non-medical costs (transportation and food while at health facility). Indirect costs reflected the value of the time lost due to attending an ANC visit. While direct costs reflect the financial costs, the economic costs include both direct and direct costs. The average household cost of malaria prevention per pregnancy was calculated by multiplying the cost of providing malaria prevention services through an ANC visit by the average number of IPTp doses received ¹² .

Women who reported having experienced an episode of malaria in their current pregnancy (n=434) (Table S1 ¹⁴ ), were asked about the direct (medical and non-medical) and indirect (value of time lost because of illness) costs associated to malaria treatment they had incurred. Uncomplicated malaria was defined as a confirmed malaria episode diagnosed at the outpatient clinic and not requiring hospital admission, while complicated malaria was defined as an episode of malaria requiring hospital admission. For inpatients cases, women were asked about the costs incurred during hospitalization, length of stay and the presence of a caregiver while hospitalized and after discharge at home. The monetary value of women’s time lost was estimated by taking into consideration the average wage by activity sector and country ( https://meusalario.org/mocambique/salario/sector-publico-mocambique/salarios-do-sector-de-saude) ^{15– 21} . For unemployed participants, studying or working in the informal sector, the minimum wage per country was considered. For women who had a caregiver while being admitted at the hospital or at home, the caregiver’s value of time lost was also included.

The health system costs associated to preventing malaria were retrieved and consist of the provision of IPTp and ITNs at the ANC visits. These costs included the costs of IPTp treatment with SP, the distribution of ITNs at the first ANC visit, personnel time and facilities running costs. Health personnel costs and health facility running costs were allocated to malaria prevention services based on an assessment of the proportion of time devoted to these services during an ANC visit. Reference prices for drugs and mosquito nets were taken from WHO and the Global Fund procurement prices. The average prevention costs per pregnancy were approximated by multiplying the costs of an ANC visit by the average number of IPTp doses received per women in intervention areas ¹² .

In addition, the health system costs of treating an episode of MiP, both for uncomplicated and complicated malaria, were estimated. The average cost of an uncomplicated case was defined as the costs of managing a malaria case in pregnancy as an outpatient, while the average costs of a complicated malaria episode were approximated by the average cost of a hospital admission case.

Recurrent (personnel salaries and time, medical supplies, etc.) and capital costs (utilities and running costs) associated with malaria treatment in pregnancy were estimated based on the average time and clinical staff involved in the management of MiP. WHO and the Global Fund procurement prices were used as reference prices for drugs, tests and vaccines ^{22, 23} . To estimate health facilities’ running costs, overall monthly expenses were allocated to a malaria case or an ANC visit, based on the proportion of malaria episodes or ANC visits of the total of outpatient visits. For health facilities with inpatient services (n=30), the cost per inpatient bed day was obtained from the WHO estimates ²⁴ . Total admission costs were calculated by multiplying the cost per inpatient bed day by the average number of admission days reported.

The societal cost of malaria care per pregnancy was estimated by including the costs of malaria prevention and treatment to the health system and households. The average treatment costs per pregnancy, both for the health system and households, were calculated by multiplying the treatment costs per malaria case (complicated and non-complicated) by the incidence of malaria (complicated and non-complicated) in pregnancy. We approximated the incidence of MiP by using self-reported data from pregnant women in intervention areas (Table S1 ¹⁴ ).

Data was collected through standardized questionnaires using REDCap and data was directly entered after asking questions verbally to participants. Alternative applications to REDCap which are available for free include Qualtrics, among others. Stata 17 and Microsoft Excel 2019 were used to perform the costing calculations. Spearman’s rank correlation coefficient was used to assess the association between households’ time lost and overall costs associated to malaria control and treatment in pregnancy.

Out of the 2,617 pregnant women approached, 2,031 met the inclusion criteria and were interviewed (Table S1 ¹⁴ ). The mean participant’s age was 24 years (SD 6.4), with more than 80% of them being married or in union (Table S2 ¹⁴ ). Most of the participants worked as subsistence farmers, except in NGA where almost 45% of respondents worked as small-scale traders or self-employed workers. The level of education varied by country, with DRC having the highest share of respondents with secondary and higher studies accomplished (67.7%), and Mozambique the lowest (9.6%). The percentage of women reporting having experienced an episode of malaria in their current pregnancy ranged between 8.8% in Madagascar and 42.7% in Nigeria.

Table 1 shows household costs associated to malaria prevention in pregnancy. The average household costs of attending an ANC visit, where malaria preventive measures in pregnancy are provided, such as ITNs or IPTp, were multiplied by the average IPTp doses received, resulting in average household prevention costs per pregnancy of USD6.33 in DRC, USD10.06 in MDG, USD15.03 in MOZ and USD13.33 in NGA. The indirect cost – time lost due to attending an ANC visit, with an average time loss of 3.5 hours/ANC visit – was the main contributor.

Overall, out of the 2,031 interviewed pregnant women, 73 (4%) experienced an episode of complicated malaria in their current pregnancy and 361 (18%) referred to having had an episode of uncomplicated malaria (Table S1 ¹⁴ ). Household average cost associated with an episode of uncomplicated malaria was USD22.78 in DRC, USD16.65 in MDG, USD30.54 in MOZ and USD18.92 in NGA ( Table 2). Regarding complicated malaria, household costs were USD35.65 in MDG, USD44.71 in NGA, USD46 in DRC and USD61.25 in MOZ ( Table 3).

The indirect cost of treatment was the highest cost, both for complicated and uncomplicated malaria episodes ( Table 2, Table 3 and Table S3 ¹⁴ ). In Figure 1 and Figure 2, the plots of the total minutes lost due to an ANC visit ( Figure 1) and the days lost due to an episode of malaria ( Figure 2) against the overall households’ costs are shown. In both plots there is a strong association between the time lost and the overall households’ costs, with a Spearman’s rank correlation coefficient of 0.73.

Out-of-pocket (OOP) expenses, particularly the direct medical expenses associated to treatment and prevention of malaria in pregnancy, were found to be present across study countries ( Table 2 and Table 3). More specifically, 22% (14 out of 63) of the women interviewed in DRC, 54% (23 out of 42) in MDG, 12% (10 out of 81) in MOZ and 33% (58 out of 175) in NGA, reported direct medical expenses when having an outpatient visit related to an uncomplicated malaria episode (e.g., tests, drugs and registration fees). For the admission cases, all women reported having incurred in direct medical expenses in all study sites.

The health centres included in the survey were all part of the public health system but significantly differed in terms of population catchment area, human resources and equipment (Table S4 ¹⁴ ). Among selected health facilities, 23% (30 out of 133) had the resources to treat an episode of complicated malaria in pregnancy (i.e., inpatient services), while in 77% of them (103 out of 133) patients with complicated malaria had to be transferred to the district hospital or other referral centres.

Table 4 presents the health system costs of preventing MiP through the ANC visits. The average health system costs per pregnancy were USD10.74 in DRC, USD16.95 in MDG, USD11.17 in MOZ and USD15.64 in NGA. Drugs (IPTp treatment with SP) constituted the largest share of cost, followed by insecticide treated nets (ITNs).

Provider costs for the treatment of an uncomplicated malaria episode in pregnancy were USD4.69 in DRC, USD3.61 in MDG, USD4.68 in MOZ and USD4.09 in NGA ( Table 5). Case management of uncomplicated malaria was similar across study countries, with rapid diagnostic test (RDTs) being used as the main diagnostic tool, and artemether-lumefantrine as the main first-line drug for treatment of uncomplicated malaria (Table S5 ¹⁴ ).

Regarding complicated malaria, the treatment costs per episode were USD101.41 in DRC, USD63.33 in MDG, USD83.70 in MOZ and USD92.64 in NGA ( Table 6). Differences in costs across countries were due to differences in hospital admission costs and number of admission days, with total admission costs per malaria case of USD88.16 in DRC, USD47.49 in MDG, USD64.20 in MOZ and USD77.33 in NGA ( Table 6). Further details on the management of a complicated malaria episodes in pregnancy are presented in supplementary Table S6 ¹⁴ ).

As presented in Table 7, mean societal costs of malaria prevention and treatment per pregnancy were USD31.72 in DRC, USD29.77 in MDG, USD31.98 in MOZ and USD46.16 in NGA. If we assume that the proportion of pregnant women represents 4% of the total population, this would translate, for a targeted area with 100,000 inhabitants, into a yearly economic burden of malaria in pregnancy of USD126,874 in DRC, USD119,083 in MDG, USD127,901 in MOZ and USD184,620 in NGA.