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      Economic Evaluation of an Alternative Drug to Sulfadoxine-Pyrimethamine as Intermittent Preventive Treatment of Malaria in Pregnancy

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          Abstract

          Background

          Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended in HIV-negative women to avert malaria, while this relies on cotrimoxazole prophylaxis (CTXp) in HIV-positive women. Alternative antimalarials are required in areas where parasite resistance to antifolate drugs is high. The cost-effectiveness of IPTp with alternative drugs is needed to inform policy.

          Methods

          The cost-effectiveness of 2-dose IPTp-mefloquine (MQ) was compared with IPTp-SP in HIV-negative women (Benin, Gabon, Mozambique and Tanzania). In HIV-positive women the cost-effectiveness of 3-dose IPTp-MQ added to CTXp was compared with CTXp alone (Kenya, Mozambique and Tanzania). The outcomes used were maternal clinical malaria, anaemia at delivery and non-obstetric hospital admissions. The poor tolerability to MQ was included as the value of women’s loss of working days. Incremental cost-effectiveness ratios (ICERs) were calculated and threshold analysis undertaken.

          Results

          For HIV-negative women, the ICER for IPTp-MQ versus IPTp-SP was 136.30 US$ (2012 US$) (95%CI 131.41; 141.18) per disability-adjusted life-year (DALY) averted, or 237.78 US$ (95%CI 230.99; 244.57), depending on whether estimates from Gabon were included or not. For HIV-positive women, the ICER per DALY averted for IPTp-MQ added to CTXp, versus CTXp alone was 6.96 US$ (95%CI 4.22; 9.70). In HIV-negative women, moderate shifts of variables such as malaria incidence, drug cost, and IPTp efficacy increased the ICERs above the cost-effectiveness threshold. In HIV-positive women the intervention remained cost-effective for a substantial (up to 21 times) increase in cost per tablet.

          Conclusions

          Addition of IPTp with an effective antimalarial to CTXp was very cost-effective in HIV-positive women. IPTp with an efficacious antimalarial was more cost-effective than IPTp-SP in HIV-negative women. However, the poor tolerability of MQ does not favour its use as IPTp. Regardless of HIV status, prevention of malaria in pregnancy with a highly efficacious, well tolerated antimalarial would be cost-effective despite its high price.

          Trials Registration

          ClinicalTrials.gov NCT 00811421; Pan African Trials Registry PACTR2010020001429343 and PACTR2010020001813440

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          Most cited references 43

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          Quantifying the Number of Pregnancies at Risk of Malaria in 2007: A Demographic Study

          Introduction Malaria in pregnancy can have devastating consequences to a pregnant woman and the developing fetus, but comprehensive estimates of the annual number of women who become pregnant each year in malaria endemic areas and are therefore at risk of malaria are not available, particularly for Latin America and the Asia-Pacific regions. These figures are an important first step towards informing policy makers and for estimating the regional needs for therapeutic and disease prevention tools for malaria in pregnancy. The most cited global estimate is from the Roll Back Malaria Partnership, which states that “each year approximately 50 million women living in malaria endemic countries throughout the world become pregnant” [1]. However, an explanation of the methods used to derive these estimates is not provided. More comprehensive estimates exist for Africa and are provided by the Africa Regional Office (AFRO) of the World Health Organization (WHO) in their widely quoted strategic framework document for malaria prevention and control during pregnancy in the African region [2]. Their estimate of 24.6 million pregnancies at risk of malaria (predominantly P. falciparum), is based on the number of live born babies delivered in malarious areas of Africa in the year 2000 using a combination of malaria risk maps [3] and estimates of the number of live births from UNICEF [4]. A more recent estimate by the WHO states that “In Africa, 30 million women living in malaria endemic areas become pregnant each year” [5]. Estimates for outside of Africa are less clear, particularly for P. vivax. P. vivax is the most widely distributed human malaria parasite and co-occurs with P. falciparum in tropical areas but also occurs in temperate regions outside the limits of P. falciparum transmission. It is the major cause of malaria in much of Asia and Latin America [6],[7], and recent evidence has shown that P. vivax infections are far from benign and can result in significant morbidity in pregnant women with serious consequences for maternal and infant health [8]–[10]. Here we define a global estimate of the number of pregnancies at risk of P. falciparum and P. vivax malaria in 2007 by combining malaria spatial limits developed by the Malaria Atlas Project (MAP; www.map.ox.ac.uk), which define the total population at risk of malaria [11], with country-specific demographic data on women of childbearing age provided by the United Nations and published data on induced abortions and spontaneous pregnancy loss. Methods Data Sources The global limits of P. falciparum malaria The initial focus of the Malaria Atlas Project has been P. falciparum [12] due to its global epidemiological significance [13] and better prospects for its control and local elimination [14]. The global spatial limits of P. falciparum malaria transmission in 2007 have recently been mapped. This was done by triangulating data on transmission exclusion using biological rules based on temperature and aridity limits on the bionomics of locally dominant Anopheles vectors, data on nationally reported case incidence rates, and other medical intelligence [15]. The resulting map stratifies the malaria endemic world by stable and unstable transmission in 2007 [15]. Unstable transmission refers to areas where transmission is plausible biologically, but limited, with a clinical incidence of less than one case per 10,000 population per year. Stable transmission refers to areas with a minimum of one clinical case per 10,000 population per year [15]. The global limits of P. vivax malaria Initial attempts to map the limits of P. falciparum and P. vivax transmission were made by Guerra et al. [16],[17]. The resulting maps and “masks” (mapped areas that are filtered and excluded from analyses) used were later tested against the Malaria Atlas Project parasite prevalence database to assess their feasibility [18],[19]. This testing revealed that the accuracy to define areas of zero transmission risk due to very low population densities was limited because of the coarse spatial resolution of the initial map. Moreover, in the initial mapping [16],[17], a high density population mask was used on the basis of the assumption that no transmission occurs in areas where the population density is so high that conditions become unsuitable for transmission through the process of urbanization. However, recent analyses [19] provide evidence suggesting that high density population masks and urban extent maps should not be used to map zero risk because some transmission can occur in high density urban areas, although this is significantly lower than in rural areas [18],[19]. Therefore, for the current analyses, the P. vivax limits were redefined using the same methods as in Guerra et al. [16],[17], but without applying the population-based masks. Also, previously excluded P. vivax endemic countries have now been added after a more extensive review of the literature; these include Comoros, Djibouti, Madagascar, and Uzbekistan. This refinement of the spatial limits of transmission for P. vivax accounted for an approximate 19% increase in the population at risk (PAR) compared with previous estimates [16],[17], principally (18%) due to the inclusion of major cities. Gridded population data The Global Rural-Urban Mapping Project (GRUMP) alpha version provides gridded population counts and population density estimates for the years 1990, 1995, and 2000, both adjusted and unadjusted to the United Nations' national population estimates [11],[20]. The adjusted population counts for the year 2000 were projected to 2007 by applying national, medium variant, intercensal growth rates by country [21] using methods described previously [22]. Annual number of pregnancies per country The number of pregnancies was calculated as the sum of the number of live births, induced abortions, and spontaneous pregnancy loss (including miscarriages and stillbirths) in 2007. Live births The annual number of live births in 2007 was estimated per country using demographic data on the proportion of women of childbearing age (WOCBAs) within a population and the total fertility rates. The data were abstracted from the United Nations' national population estimates, which provide publicly accessible demographic information by year, age, sex, and country for Africa, Asia, and the Americas [23]. The number of WOCBAs in each country, defined as the mid-year resident number of women aged between 15 and 49y, was obtained for the years 2005 and 2010 (interim years are not available), and the number of WOCBAs for 2007 was calculated as the midpoint between the 2005 and 2010 estimates. The fraction of WOCBAs per country was then calculated as the number of WOCBAs in 2007 divided by the mid-year resident population at risk in 2007 (available by year). The total fertility rate (TFR) is an age-standardised measure of fertility and corresponds to the total number of children that would be born alive to a woman entering her childbearing years at age 15y if she lived to the end of her childbearing years (age 49y) and if her fertility during these 35 reproductive years was the same as the average woman of childbearing age. The total fertility rate divided by 35 is the average number of live births per WOCBA per year and when multiplied by 1,000 this is expressed as the rate of live births per 1,000 WOCBAs per year. Induced abortions, miscarriages, and stillbirth rates Subregional data on induced abortion rates were obtained from a recently published review that calculated the worldwide, regional, and subregional incidence of safe and unsafe abortions in women of child bearing age in 2003 by use of reports from official national reporting systems, nationally representative demographic health surveys, hospital data, other surveys, and published studies [24]. Country-specific information on stillbirth rates was abstracted from model-based estimates published by Stanton et al. [25] that derived data from vital registration, demographic and health surveys (DHS), and data from study reports integrated into a regression model. Regional estimates were used for three malaria endemic countries for which country-specific estimates were not available (French Guiana, Mayotte, and Timor-Leste). Country-specific data on miscarriages (spontaneous abortions) are not available. To calculate the proportion of pregnancies resulting in miscarriage, a method was applied that uses multipliers to work backwards from the (known) number of live births and induced abortions to recover the (unknown) underlying number of pregnancies that “produced” them, as described in detail previously [24],[26]–[28]. The method takes account of pregnancies that are terminated voluntarily during the period of risk for miscarriage and estimates the number of spontaneous pregnancy loss (stillbirths and miscarriages) as 10% of induced abortions plus 20% of live births. It is based on clinical studies of rates of pregnancy loss by gestational age that indicate that for each 100 induced abortions an additional ten clinically recognised pregnancies will have aborted spontaneously prior to the average gestational age of induced abortions in that population, and that approximately 120 additional clinically recognised pregnancies are required to “produce” 100 live births [27],[28]. For example, in Afghanistan it was estimated that in 2007 1.182 million live births occurred among a population of 27 million and a further 0.284 million induced abortions occurred. The number of spontaneous pregnancy losses (the sum of the number of stillbirths and miscarriages) was therefore estimated at 0.2×1,182 plus 0.1×0.284 = 0.265 million, and the total number of pregnancies as 1.731 million. The reported number of miscarriages used in this manuscript represents the number of spontaneous pregnancy losses calculated through the multiplier method as described above, minus the country-specific number of stillbirths obtained from the review by Stanton et al. [25]. The estimates provided in this study refer to clinically recognised pregnancies and do not take into account the potentially large but unknown rates of embryonic loss that may occur in the first 4–6 wk of gestation. Estimating the annual number of pregnancies exposed to malaria To obtain the total population at risk, the limits of stable and unstable P. falciparum transmission and the limits of P. vivax transmission described above were overlaid onto the Global Rural-Urban Mapping Project (GRUMP) alpha surface, projected to 2007. For every malaria endemic country of the world, the population within each set of limits was extracted, following approaches described previously [13]. The number of pregnancies at risk of malaria was then calculated from the total annual number of pregnancies estimated to have occurred in 2007 in the entire country multiplied by the fraction of the total resident population living within the spatial limits of malaria transmission in that country. Results Tables 1 and 2 provide a summary of the total population living within the global spatial limits of malaria transmission in 2007, and the corresponding number of total population, pregnancies, and live births, stratified by species and transmission patterns (within areas of assumed unstable and stable P. falciparum transmission), globally and by WHO region. 10.1371/journal.pmed.1000221.t001 Table 1 Demographic data for malaria endemic countries. WHORO Region n of MECs Total Population (Both Sexes)a WOCBAsa Total n of Pregnanciesb TPRc Pregnancy Rate per 1,000 WOCBAs§ Percentage Pregnancies Ending in: Live-births Still-births Spontaneous Abortions Induced Abortions AFRO 43 755 178 36 7.16 204 72.4% 2.3% 13.3% 11.9% EMRO/EURO 19 544 142 19 4.76 136 68.8% 2.3% 13.1% 15.8% AMRO 21 530 143 16 3.81 109 63.2% 0.9% 14.0% 22.0% SEARO/WPRO 19 3,327 881 91 3.62 103 62.4% 1.6% 13.1% 22.8% Global 102 5,157 1,343 162 4.23 121 65.5% 1.8% 13.3% 19.5% a Source: United Nations Development Program (in millions). b The total number of pregnancies is the sum of the number of live-births, stillbirths, spontaneous, and induced abortions (in millions). c The total pregnancy rate (TPR) and the annual pregnancy rate per 1,000 WOCBAs are weighted means per region and is for illustration purposes only. The number of pregnancies was derived directly as the sum of the national estimates within each region and globally. MEC, malaria endemic countries; WHORO, World Health Organization Regional Office. 10.1371/journal.pmed.1000221.t002 Table 2 Total population at risk of P. falciparum and/or P. vivax malaria by WHO regional office in 2007 (in millions) (percent of the population in malaria endemic countries at risk). WHORO Region P. falciparum Transmissiona P. vivax Transmissiona Any Species Stable Transmissionb Unstable Transmissionb Overall Overall Overall AFRO 599.9 (79.4) 8.4 (1.1) 607.8 (80.5) 73.2 (9.7) 615.4 (81.5) EMRO/EURO 89.8 (16.5) 101.7 (18.7) 190.9 (35.1) 285.1 (52.4) 343.9 (63.2) AMRO 41.2 (7.8) 50.2 (9.5) 91.4 (17.2) 96.2 (18.2) 138.2 (26.1) SEARO/WPRO 654.9 (19.7) 824.9 (24.8) 1479.3 (44.5) 2,722.3 (81.8) 2,770.1 (83.3) Global 1,385.8 (26.9) 985.1 (19.1) 2,369.4 (45.9) 3,176.9 (61.6) 3,867.6 (75.0) Similar tables with risk estimates by continent and by pregnancy outcome (live-birth, induced abortions, stillbirths, and miscarriages) are provided in Tables S1, S2, S3. a Includes countries where P. falciparum and P. vivax co-exist. b Stable transmission, ≥1 autochthonous P. falciparum cases per 10,000 people per annum; unstable transmission, <1 autochthonous P. falciparum cases per 10,000 people per annum [15]. MEC, malaria endemic countries; TPR, total pregnancy rate; WHORO, World Health Organization Regional Office. The compiled data showed that, globally, 125.2 million women living in areas with P. falciparum and/or P. vivax transmission became pregnant in 2007: 77.4 million (61.8%) in the countries that fall under the regional office of the WHO for the South East Asian (SEARO) and the Western Pacific Region (WPRO); 30.3 million (24.2%) in AFRO; 13.1 million (10.5%) in the Eastern Mediterranean and European Region (EMRO and EURO); and only 4.3 million (3.4%) in the American Region (AMRO) (Table 3). Figures 1 and 2 display the same analysis by species, but depicted by continent rather than by WHO region. Of the 125.2 million pregnancies, 82.6 million (66.0%) are estimated to result in live births; 48.8 million (63.0%), 22.1 million (72.7%), 9.0 million (68.8%), and 2.7 million (63.1%) in the SEARO/WPRO, AFRO, EMRO/EURO, and AMRO regions, respectively (Table 4). It illustrates that the proportional distribution of pregnancies at risk resulting in live births is slightly different from the distribution of total pregnancies at risk, primarily reflecting the differences in the proportion of pregnancies ending in induced abortions, which is much lower in the AFRO region (11.9%) compared to the global average in the malaria endemic countries of 19.5% [24]. 10.1371/journal.pmed.1000221.g001 Figure 1 Malaria risk map for P. falciparum and corresponding number of pregnancies in each continent in 2007. 10.1371/journal.pmed.1000221.g002 Figure 2 Malaria risk map for P. vivax and corresponding number of pregnancies in each continent in 2007. 10.1371/journal.pmed.1000221.t003 Table 3 Number of pregnancies at risk of P. falciparum and/or P. vivax malaria by WHO regional office in 2007 (in millions) (column %). WHORO Region P. falciparum Transmissiona P. vivax Transmissiona Any Species Stable Transmissionb Unstable Transmissionb Overall Overall Overall AFRO 29.6 (54.1) 0.4 (1.2) 30.0 (35.1) 3.6 (3.9) 30.3 (24.2) EMRO/EURO 4.0 (7.3) 4.2 (13.7) 8.2 (9.6) 10.4 (11.2) 13.1 (10.5) AMRO 1.4 (2.5) 1.6 (5.2) 3.0 (3.5) 2.9 (3.1) 4.3 (3.4) SEARO/WPRO 19.7 (36.1) 24.5 (79.9) 44.2 (51.8) 76.0 (81.8) 77.4 (61.8) Global 54.7 30.6 85.3 92.9 125.2 Similar tables with risk estimates by continent and by pregnancy outcome (live-birth, induced abortions, stillbirths, and miscarriages) are provided in Tables S1, S2, S3. a Includes countries where P. falciparum and P. vivax co-exist. b Stable transmission, ≥1 autochthonous P. falciparum cases per 10,000 people per annum; unstable transmission, <1 autochthonous P. falciparum cases per 10,000 people per annum [15]. MEC, malaria endemic countries; TPR, total pregnancy rate; WHORO, World Health Organization Regional Office. 10.1371/journal.pmed.1000221.t004 Table 4 Number of live-births born to pregnancies at risk of at risk of P. falciparum and/or P. vivax malaria by WHO regional office in 2007 (in millions) (column %). WHORO Region P. falciparum Transmissiona P. vivax Transmissiona Any Species Stable Transmissionb Unstable Transmissionb Overall Overall Overall AFRO 21.6 (56.7) 0.3 (1.3) 21.8 (37.4) 2.5 (4.3) 22.1 (26.7) EMRO/EURO 2.8 (7.3) 2.9 (14.1) 5.6 (9.7) 7.1 (12.0) 9.0 (10.9) AMRO 0.8 (2.2) 1.0 (5.0) 1.8 (3.2) 1.8 (3.1) 2.7 (3.3) SEARO/WPRO 12.9 (33.8) 16.1 (79.5) 28.9 (49.7) 48.0 (80.6) 48.8 (59.1) Global 38.0 20.2 58.2 59.5 82.6 Similar tables with risk estimates by continent and by pregnancy outcome (live-birth, induced abortions, stillbirths, and miscarriages) are provided in Tables S1, S2, S3. a Includes countries where P. falciparum and P. vivax co-exist. b Stable transmission, ≥1 autochthonous P. falciparum cases per 10,000 people per annum; unstable transmission, <1 autochthonous P. falciparum cases per 10,000 people per annum [15]. MEC, malaria endemic countries; TPR, total pregnancy rate; WHORO, World Health Organization Regional Office. P. falciparum Malaria Of the 125.2 million pregnancies defined above, 85.3 million occur in areas with P. falciparum transmission, 51.8% of them (44.2 million) are in the combined SEARO-WPRO regions and 35.1% (30.0 million) in the AFRO region. The remainder live in the EMRO-EURO (9.6%) and AMRO regions (3.5%) (Figure 3; Table 3). As expected, the top five ranked countries with the highest number of pregnancies at risk of P. falciparum malaria were the malaria endemic countries with the largest overall populations: India (28.2 million), Nigeria (6.5 million), Indonesia (4.4 million), Pakistan (3.7 million), and the Democratic Republic of the Congo (3.3 million). Overall, 64.1% of 85.3 million pregnancies at risk of P. falciparum malaria live in areas with assumed stable transmission (Figure 3). However, this varies widely by region; from 98.7% in the AFRO region to none in the EURO region. As depicted in Figure 3, 55.3% of the 44.2 million pregnancies at risk of P. falciparum in the WPRO/SEARO region occur in areas of very low and unstable transmission. 10.1371/journal.pmed.1000221.g003 Figure 3 Distribution of the number of pregnancies in areas with P. falciparum malaria in 2007 by WHO regions and the corresponding proportion living under stable versus unstable transmission. Blue, SEARO and WPRO; green, AFRO; orange, EMRO; red, AMRO. P. vivax Malaria Globally, an estimated 92.9 million pregnancies occurred in areas endemic for P. vivax in 2007 (including in areas where both P. falciparum and P. vivax co-exist) (Figure 2). The top five ranked countries include: India (32.9 million), China (21.2 million), Indonesia (6.3 million), Pakistan (5.8 million), and Bangladesh (4.7 million). In the WPRO/SEARO region, where the majority of the populations at risk of P. vivax live (Figure 4), approximately 98.2% of those pregnancies in malaria endemic countries occur in areas with P. vivax transmission (alone or combined with P. falciparum). By contrast this was only 11.9% for the AFRO region where P. vivax transmission is principally restricted to the horn of Africa region, Madagascar, and the Comoros islands (Figure 4). 10.1371/journal.pmed.1000221.g004 Figure 4 Distribution of the number of pregnancies in malaria endemic areas in 2007 by WHO regions and by species (P. vivax transmission only, P. falciparum transmission only or transmission of both species). Blue, SEARO and WPRO; green, AFRO; orange, EMRO; red, AMRO. Pv, P. vivax; Pf, P. falciparum. The country-specific demographic data and population at risk estimates (Table S1), as well as total pregnancies at risk and by specific pregnancy outcomes (live births, induced abortions, stillbirths, and miscarriages; Table S2) and summary estimates by other regional categories (continents instead of WHO regions; Table S3), are provided as supplemental information. In addition, information is provided illustrating which countries are included in the different WHO regions (also see Figure S1) [29]. In brief, all malaria endemic countries on the African continent fall under the Africa Regional Office (AFRO), with the exception of Djibouti, Somalia, and Sudan, which fall under the EMRO office. Discussion This is the first time, to our knowledge, that contemporary species-specific estimates of the annual number of pregnancies at risk of malaria globally have been made. Our findings suggest that in 2007 approximately 125 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission, resulting in 83 million live births; representing approximately 60% of all pregnancies globally. Approximately 85 million pregnancies occurred in areas with P. falciparum transmission and 93 million in areas with transmission of P. vivax transmission, of which about 53 million occurred in areas where both species co-exist. The pregnancies at risk estimates for P. falciparum and P. vivax in Africa (32 million [30 million in the WHO-AFRO region]) are consistent with the previous estimates by WHO (25–30 million). By contrast, the numbers at risk outside Africa are much higher (95 million) than previously estimated (25 million). Comparisons between the estimates produced in this study and the previous WHO estimates are made difficult because details of the methodology used by the WHO is not provided and it is not clear if they included all transmission areas or only areas with stable malaria transmission. Inclusion of only those areas with stable P. falciparum transmission in our study resulted in global risk estimates of just less than 55 million pregnancies, 31 million in Africa and 23 million in the other regions, i.e., very similar to the previous WHO estimates. However, the numbers of pregnancies at risk outside Africa increase almost 4-fold if areas with unstable P. falciparum transmission are included (clinical incidence <1 per 10,000 population/year) (30 million) and areas situated in the temperate regions outside the limits of P. falciparum transmission that have P. vivax transmission only (40 million) are also included. It is also not clear if the previous WHO estimates included pregnancies resulting in live births only or included adjustments for induced abortions or spontaneous pregnancy loss. Since only approximately two-thirds of all pregnancies result in live births, estimates that include all pregnancies are about one-third higher than estimates based on live births only. Although risk estimates are widely quoted figures, it is important to place them in perspective. The estimates provided here merely define the global distribution of pregnancies that occur within the global spatial limits of malaria transmission. These estimates therefore represent “any risk” of exposure to malaria during pregnancy, and do not represent the distribution of actual incidence or health burden on mothers and unborn babies, which is beyond the scope of this paper. More than half (71 million) of the 125 million pregnancies occur in areas with unstable P. falciparum transmission (31 million) or with transmission of P. vivax only (40 million), and the risk of acquiring malaria in these areas is extremely low. Thus, although these 71 million pregnancies represent more than 50% of the global number of pregnancies at risk, they may only contribute a small proportion to the number of infections in pregnancy. For example, if the actual incidence of malaria infection in these very low transmission areas is 1 in 10,000 per person-year (52 wk), and if the average pregnancy resulting in a live birth takes 38 wk from fertilisation to term, then 71 million pregnancies at risk may result in only 5,188 actual malaria infections, whereas in areas with infection rates of 1.36 or higher per person-year, all term pregnancies have been potentially exposed to malaria. Furthermore, the definition of stable transmission for P. falciparum used included all areas with more than one clinical case per 10,000 population per year. This included almost all pregnancies at risk in the AFRO Region (99% of the 30 million pregnancies at risk) and 25 million of the 95 million (26%) pregnancies in the other WHO regions. However, these stable transmission strata cover a very wide range of transmission intensities and the actual risk of infection to the 55 million individuals and the impact on maternal and infant health varies enormously within this range. At the higher end of the transmission spectrum, the majority of malaria infections in pregnancy remain asymptomatic or pauci-symptomatic, yet are a major cause of severe maternal anaemia and preventable low birth weight, especially in the first and second pregnancies. In areas with stable, but low transmission, and certainly in areas with unstable and exceptionally low transmission, infections can become severe in all gravidae groups because most women of childbearing age in these regions have low levels of pre-pregnancy and pregnancy-specific protective immunity to malaria [30]. The most recent version of the World Malaria Map [28] from the Malaria Atlas Project shows that 89% of the populations in stable P. falciparum areas outside Africa live in areas characterised by low malaria endemicity (defined as P. falciparum parasite rate in children 2–10 y of age of ≤5%). This total includes all of the stable P. falciparum transmission areas in the Americas, and 88% of the populations at risk in the Central and South-East Asia-Pacific region [31]. Our estimates do not take seasonality into account and include all pregnancies occurring throughout the year, whereas those pregnancies that occur outside of the transmission season may be at no risk, or very low risk of exposure. Our risk estimates for P. vivax are likely to be less accurate than those for P. falciparum because of greater uncertainties about the basic biology of transmission and clinical epidemiology. For example, the climatic constraints on P. vivax transmission are less well defined, the accuracy of clinical reporting of P. vivax in areas with coincidental P. falciparum is poor, and the untreated hypnozoite stage of P. vivax, which can remain dormant in infected liver cells for months or years, provides an additional challenge to the interpretation of prevalence and incidence data [15]. We used a refined P. vivax risk map that resulted in a 19% increase over previous population at risk estimates (adjusted for population growth) [18],[19], principally resulting from the removal of the population density masks and thereby the inclusion of many large cities. In most of these cities, pregnancies will be at low or very low risk of autochthonous infections. Imported malaria associated with travel to rural areas may be a greater risk factor in these cities. We did not consider infections with P. ovale or P. malariae, as their distribution is not well described and the adverse effects on maternal health and the newborn infant are unknown. In the current analysis we used the map of the global spatial limits of P. falciparum malaria, which stratifies the malaria endemic world by stable and unstable transmission published in 2008 [15].This map uses a simple divide between very low risk and higher transmission intensities and a crude proxy to account for the corresponding levels of acquired immunity in women of childbearing age. As a next step, we will examine the burden of malaria in pregnancy in terms of health impact on the pregnant women (e.g., febrile episodes, impact on maternal anaemia and maternal mortality), the newborn baby (e.g., impact on the frequency of preterm births and low birth-weight) and the infant (e.g., susceptibility to malaria). For this project, we will use the more refined P. falciparum transmission intensity model of risk within the defined stable limits which was developed recently by the Malaria Atlas Project [31], allowing disease impact calculations across multiple transmission strata to be made. It is also important to take the different pregnancy outcomes into account in these further burden estimates. Of the 125 million pregnancies, one in five are estimated to be terminated voluntarily during the period of risk for miscarriage, and only about two-thirds (82.6 millions) are expected to result in live births. Although malaria in pregnancy is associated with miscarriages and stillbirths [30], the majority of the health and economic burden is likely through the impact on pregnancies that result in live births by increasing the risk of preterm births and low birth-weight [30] and by modifying the susceptibility to malaria in the infant [32]–[34]. Most of the existing research and policy guidance for malaria control in pregnancy has focussed on P. falciparum in the stable transmission regions of sub-Saharan Africa. The results of this study are consistent with the previous WHO-RBM risk estimates for areas with stable P. falciparum malaria in Africa, but our work offers advancement on the existing risk estimates for malaria endemic countries outside Africa. In these regions, the burden of malaria in pregnancy is less well defined, both in terms of the number of pregnancies and its actual impact on health. Policy guidelines for malaria control in pregnancy are also less well developed for these regions. These estimates of the number of pregnancies at risk of malaria provide a first step towards a spatial map of the burden of malaria in pregnancy and a more informed platform with which to estimate the associated disease and economic impact and its geographical distribution. Such global estimates provide guidance in terms of priority setting for resource allocation for both research and policy for the control of malaria in pregnancy. This project provides a dynamic framework that allows risk estimates to be updated when new risk maps of P. falciparum and P. vivax become available as the world attempts to move towards malaria elimination and eradication. Supporting Information Figure S1 Map of the WHO Regions (http://www.who.int/about/regions/en/index.html). (1.07 MB TIF) Click here for additional data file. Table S1 Demographic characteristics and total population at risk of P. falciparum and/or P. vivax malaria by malaria endemic country and by WHO regional office in 2007 (in millions). (0.38 MB PDF) Click here for additional data file. Table S2 Total number of pregnancies by pregnancy outcome in areas with P. falciparum and/or P. vivax transmission by continent in 2007 (in millions). (0.54 MB PDF) Click here for additional data file. Table S3 Total population, number of pregnancies, and number of live-births born to pregnancies in malaria endemic countries by continent in 2007 (in millions). (0.28 MB PDF) Click here for additional data file.
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            Model parameter estimation and uncertainty analysis: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force Working Group-6.

            A model's purpose is to inform medical decisions and health care resource allocation. Modelers employ quantitative methods to structure the clinical, epidemiological, and economic evidence base and gain qualitative insight to assist decision makers in making better decisions. From a policy perspective, the value of a model-based analysis lies not simply in its ability to generate a precise point estimate for a specific outcome but also in the systematic examination and responsible reporting of uncertainty surrounding this outcome and the ultimate decision being addressed. Different concepts relating to uncertainty in decision modeling are explored. Stochastic (first-order) uncertainty is distinguished from both parameter (second-order) uncertainty and from heterogeneity, with structural uncertainty relating to the model itself forming another level of uncertainty to consider. The article argues that the estimation of point estimates and uncertainty in parameters is part of a single process and explores the link between parameter uncertainty through to decision uncertainty and the relationship to value-of-information analysis. The article also makes extensive recommendations around the reporting of uncertainty, both in terms of deterministic sensitivity analysis techniques and probabilistic methods. Expected value of perfect information is argued to be the most appropriate presentational technique, alongside cost-effectiveness acceptability curves, for representing decision uncertainty from probabilistic analysis.
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              • Article: not found

              Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review.

              In malaria-endemic regions, strategies to control malaria during pregnancy rely on case management of malaria illness and anemia, and preventive measures such as insecticide-treated nets and intermittent preventive therapy (IPT). To determine the effect of increasing resistance to sulfadoxine-pyrimethamine on the efficacy of IPT during pregnancy in Africa. The 6 databases of MEDLINE, EMBASE, SCOPUS, LILACS, Cochrane CENTRAL, and the trial register and bibliographic database of the Malaria in Pregnancy Library were searched for relevant studies regardless of language, published between 1966 and December 2006. The reference lists of all trials identified were searched and researchers were contacted about relevant data. Nine trials of IPT with sulfadoxine-pyrimethamine during pregnancy in Africa were identified and matched by year and location with treatment studies of sulfadoxine-pyrimethamine among symptomatic children. Data on the efficacy of IPT with sulfadoxine-pyrimethamine on placental and peripheral malaria, birth weight, and hemoglobin level/anemia were independently abstracted by 2 investigators. Sulfadoxine-pyrimethamine resistance was defined as the proportion of total treatment failures in symptomatic children by day 14. Four trials compared 2-dose IPT with sulfadoxine-pyrimethamine to case management or placebo in women during their first or second pregnancy. The IPT reduced placental malaria (relative risk [RR], 0.48; 95% CI, 0.35-0.68), low birth weight (RR, 0.71; 95% CI, 0.55-0.92), and anemia (RR, 0.90; 95% CI, 0.81-0.99). The effect did not vary by sulfadoxine-pyrimethamine resistance levels (range, 19%-26%). Efficacy of IPT with sulfadoxine-pyrimethamine was lower among women using insecticide-treated nets. Three trials compared 2-dose with monthly IPT with sulfadoxine-pyrimethamine during pregnancy. Among HIV-positive women in their first or second pregnancy, monthly IPT resulted in less placental malaria (RR, 0.34; 95% CI, 0.18-0.64) and higher birth weight (mean difference, 112 g; 95% CI, 19-205 g) over the range of sulfadoxine-pyrimethamine resistance tested (8%-39%). Among HIV-negative women, there was no conclusive additional effect of monthly dosing (2 trials; 24% and 39% resistance). In areas in which 1 of 4 treatments with sulfadoxine-pyrimethamine fail in children by day 14, the 2-dose IPT with sulfadoxine-pyrimethamine regimen continues to provide substantial benefit to HIV-negative semi-immune pregnant women. However, more frequent dosing is required in HIV-positive women not using cotrimoxazole prophylaxis for opportunistic infections.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 April 2015
                2015
                : 10
                : 4
                Affiliations
                [1 ]ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic—Universitat de Barcelona, Barcelona, Spain
                [2 ]London School of Hygiene and Tropical Medicine, London, United Kingdom
                [3 ]Manhiça Health Research Center (CISM), Manhiça, Mozambique
                [4 ]Centre de Recherches Médicales de Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon
                [5 ]Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
                [6 ]Faculté des Sciences de la Santé (FSS), Université d’Abomey Calavi, Cotonou, Benin
                [7 ]Ifakara Health Institute, Dar Es Salaam, Tanzania
                [8 ]Kenya Medical Research Institute (KEMRI)/Center for Global Health Research, Kisumu, Kenya
                [9 ]Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, USA and Kisumu, Kenya
                [10 ]Institut de Recherche pour le Développement (IRD), Paris, France
                [11 ]Université René Descartes, Paris, France
                [12 ]Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria
                Glaxo Smith Kline, DENMARK
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ES CM KH. Analyzed the data: ES SF. Wrote the paper: ES SF RG KH CM. Contributed to the interpretation of the results: ES SF EM RG GM-N AM SA A. Kuwawenaruwa A. Katana MD MC MR PK LS JA KH CM.

                ‡ These authors are joint senior authors on this work.

                Article
                PONE-D-14-46876
                10.1371/journal.pone.0125072
                4410941
                25915616

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

                Page count
                Figures: 7, Tables: 4, Pages: 23
                Product
                Funding
                This study was supported by MiP Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine.
                Categories
                Research Article
                Custom metadata
                Data cannot be made available due to ethical restrictions and restrictions in the consent forms signed by participants. Data are available upon request from Clara Menendez ( clara.menendez@ 123456isglobal.org ).

                Uncategorized

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