Estimating the burden of malaria in pregnancy: a case study from rural Madhya Pradesh, India

  • Nadia Diamond-Smith1Email author,

    Affiliated with

    • Neeru Singh2,

      Affiliated with

      • RK Das Gupta3,

        Affiliated with

        • Aditya Dash4,

          Affiliated with

          • Krongthong Thimasarn5,

            Affiliated with

            • Oona MR Campbell1 and

              Affiliated with

              • Daniel Chandramohan1

                Affiliated with

                Malaria Journal20098:24

                DOI: 10.1186/1475-2875-8-24

                Received: 17 April 2008

                Accepted: 12 February 2009

                Published: 12 February 2009



                Malaria in pregnancy (MiP) is inadequately researched in India, and the burden is probably much higher than current estimates suggest. This paper models the burden of MiP and associated foetal losses and maternal deaths, in rural Madhya Pradesh, India.


                Number of pregnancies per year was estimated from the number of births and an estimate of pregnancies that end in foetal loss. The prevalence of MiP, risk of foetal loss attributable to MiP and case fatality rate of MiP were obtained from the literature. The estimated total number of pregnancies was multiplied by the appropriate parameter to estimate the number of MiP cases, and foetal loss and maternal deaths attributable to MiP per year. A Monte Carlo simulation sensitivity analysis was done to assess plausibility of various estimates obtained from the literature. The burden of MiP in tribal women was explored by incorporating the variable prevalence of malaria in tribal and non-tribal populations and in forested and non-forested regions within Madhya Pradesh.


                Estimates of MiP cases in rural Madhya Pradesh based on the model parameter values found in the literature ranged from 183,000–1.5 million per year, with 73,000–629,000 lost foetuses and 1,500–12,600 maternal deaths attributable to MiP. The Monte Carlo simulation gave a more plausible estimate of 220,000 MiP cases per year (inter-quartile range (IQR): 136,000–305,000), 95,800 lost foetuses (IQR: 56,800–147,600) and 1,000 maternal deaths (IQR: 650–1,600). Tribal women living in forested areas bore 30% of the burden of MiP in Madhya Pradesh, while constituting 18% of the population.


                Although the estimates are uncertain, they suggest MiP is a significant public health problem in rural Madhya Pradesh, affecting many thousands of women and that reducing the MiP burden should be a priority.


                In high malaria-transmission settings such as much of Africa, the primary adverse outcomes of malaria in pregnancy (MiP) are low birth-weight babies and maternal anaemia. In low-transmission settings such as India, where the population is not sufficiently exposed to malaria to develop immunity by adulthood, MiP can have more serious consequences for both the foetus and mother including spontaneous abortion, stillbirth, and maternal death [1].

                There is evidence of increasing malaria prevalence throughout India [2], which is thought to stem partially from economic development, which changes vector dynamics and human migration patterns, and partially from climate change, where recent models predict the spread of malaria into new regions [3]. Any spread of malaria in India will expose large populations, including pregnant women, to malaria [4]. A recent estimate suggests an annual incidence of malaria as high as 83 million cases per year [5]. However, there is a paucity of research into MiP in India and the lack of robust data on the burden has hampered progress in making evidence-based interventions to control MiP. This paper estimates the burden of MiP in Madhya Pradesh state in order to highlight the public health significance of MiP and to contribute to the debate on appropriate interventions to reduce the burden of MiP in India.

                Madhya Pradesh was selected because it contributes the largest proportion of malaria cases among Indian states, roughly 27% [6], recent evidence suggests that malaria is on the rise there [7], and it has a large tribal population with a relatively high birth rate. Studies in Madhya Pradesh have found that between 80–87% of malaria cases were caused by Plasmodium falciparum [7], and most research on MiP has focused on this species. Given limited data on differences in maternal and foetal outcome of P. falciparum vs. Plasmodium vivax infection, for the purposes of this paper, the two are not distinguished between.

                Rural women only are analyzed, as malaria incidence is negligible in urban areas of Madhya Pradesh. Therefore, the total population denominator only includes the rural population. Due to lack of separate data, this analysis of Madhya Pradesh includes the population of Chhattisgarh as well (Chhattisgarh became an independent state in 2000, however was previously part of Madhya Pradesh).


                The number of MiP cases per year was estimated by the following model:

                Foetal loss rate (y) = proportion of pregnancies ending in spontaneous abortion + percent of pregnancies ending in stillbirth = 0.15+ 0.04 ≃ 0.20 Proportion of pregnancies ending in live births (b) = 1-"foetal loss rate" (y) = 1-0.2 = 0.8

                Total pregnancies (TP) = Live Births (B)/b = B/0.8

                Number of pregnant women with malaria (MiP) = TP* "prevalence of malaria in Pregnancy" (MiPr)

                Foetal loss includes pregnancies lost to stillbirth and spontaneous abortion. A sensitivity analysis using a Monte Carlo simulation was done to assess the plausibility of the estimates of MiP cases obtained by this model. The Monte Carlo functions in the Berkeley Madonna Modeling Software [8] were used to test the effect of changing values of multiple parameters included in the model at once by randomly selecting from within a range of values of each variable every time the model was run to estimate the MiP cases, foetal loss and maternal deaths. The model was extended to incorporate the variation in the prevalence of malaria in tribal and non-tribal populations and in forested and non-forested regions within Madhya Pradesh.

                The following input data for the model were estimated from the literature: (1) number of live births in Madhya Pradesh; (2) prevalence of MiP; (3) rates of stillbirth, spontaneous abortion and case fatality rate for pregnant women with malaria; (4) birth rates and prevalence of malaria in tribal women; (5) birth rates and prevalence of malaria in forest and non forest areas.

                Using the 2001 census data, the number of births per year in Madhya Pradesh as a whole was estimated to be 2,287,000 [9, 10]. There are limited data on foetal loss as it is very difficult to collect data on these outcomes due to their sensitive nature and problems with recall [11]. For the purposes of this paper, foetal loss includes spontaneous abortion (defined as foetus lost before 28 weeks) and stillbirths (defined as foetus lost between 28–36 weeks). A back-calculation to the total number of pregnancies, based on known number of births and the estimate of pregnancies lost to stillbirth and spontaneous abortion was made The reported national still birth rate in India is 39/1,000 [12]. The ratio of pregnancies to births in the general population was assumed to be roughly 1.25, to take into account an estimated global spontaneous abortion rate of 15% [13] and estimated Indian stillbirth rate of 4% [12]. To focus on rural populations alone, roughly 16 million people were subtracted from the total population of Madhya Pradesh, as this is the estimated urban population from the 2001 census [10]. All outcomes from modeling are presented rounded to three significant figures since these are estimates based on 500 trials and therefore are meant to show rough averages.


                Applying the reported Annual Parasite Incidence (API) in 2006 in Madhya Pradesh, which is 1.28 cases of malaria per 1000 people per year [14], gives an estimated 2,600 cases of MiP per year. However the prevalence of MiP measured in health facility based studies in Madhya Pradesh was substantially higher, and varied remarkably ranging from 6.4% to 55% [1519] (Table 1).
                Table 1

                Prevalence of malaria in pregnancy in Madhya Pradesh

                Year of study

                Type of study

                Definition of MiP

                Prevalence of MiP

                2006 [15]

                Cohort of women attending an antenatal clinic and/or delivering in a health facility

                Presence of peripheral parasitaemia during pregnancy or at delivery




                Cohort of women delivering at two hospitals

                Placental parasitaemia

                11% (site 1)

                14% (site 2)



                Cohort of women attending ANC clinic

                Peripheral parasitaemia




                Cross sectional survey of pregnant tribal women in rural villages

                Peripheral parasitaemia


                1997–1998 [19]

                Cross sectional survey during an epidemic

                Peripheral parasitaemia


                The rates of adverse maternal and foetal outcomes in women with malaria reported from India are summarized in Table 2. The study by Konar et al [20] is hospital based and thus the reported adverse outcomes of MiP are likely to be overestimates because women with mild malaria tend to be treated as outpatients. The proportion of pregnant women developing severe disease from malaria infection is speculated at around 5%, although the exact proportion of pregnant women with malaria infection becoming severe cases is unknown. Thus the rates of maternal and foetal adverse outcomes found in hospital based studies probably relate to 5% of the self-selected pregnant women with severe malaria infection admitted to hospitals [21]. This analysis assumes that the case fatality rate for pregnant women with malaria (8.4%) observed by Konar et al [20] relates to a 5% of pregnant women with severe malaria who use hospital services, therefore, the case fatality rate in pregnant women with malaria in general will be 0.84%, or 840 maternal deaths/100,000 pregnant women with malaria.
                Table 2

                Rates of adverse pregnancy outcomes attributable to MiP in India

                Year of study

                Study population

                Sample size

                Adverse outcomes


                Spontaneous Abortion

                Still birth

                Case Fatality Rate

                2001–2002 [20]

                Pregnant women with peripheral parasitaemia at 9 health centers across India







                Pregnant women with peripheral parasitaemia delivering at a hospital





                1997–1998 [19]

                Pregnant women with peripheral parasitaemia in a tribal area during malaria epidemic





                NA: not available

                The study by Singh et al in 2002–2004 [16] was conducted in an urban teaching hospital and is therefore not generalizable to the rural populations. The study by Singh et al in 1997–98 [19] took place in a tribal population during a malaria epidemic and, therefore, estimates maternal and foetal outcomes attributable to malaria in extreme conditions.

                The estimates of cases of MiP in Madhya Pradesh obtained based on the model parameters values found in the literature, ranged from 183,000 to 1,572,000; foetal loss from 73,000 to 629,000 and maternal death from 1,500 to 12,600 (Table 3). The ranges of values of variables included in the Berkeley Madonna model to estimate the cases of MiP, foetal loss and maternal death are shown in Table 4. Even though estimates in the literature had a wider range, MiP prevalence was limited to between 2% and 14% as it is assumed that values above or below these values will be inconsistent with the current level of malaria transmission in Madhya Pradesh. Spontaneous abortion and stillbirth ranges were set 50% above and below the values reported by Konar et al [20]. For reasons discussed above, 10% of the Konar estimate for case fatality rate in pregnant women with malaria (8.4%) was used, and the range varied from half to twice that amount [20]. The ranges of MiP, births in MiP, maternal deaths and foetal loss due to MiP derived from running the model 500 times is shown in (Figure 1 and Table 5). Median annual values estimated were 220,000 for MiP cases, 19,800 stillbirths, 76,000 spontaneous abortions and 1,000 deaths in pregnant women with malaria.
                Table 3

                Estimates of annual cases of MiP, and fetal loss and maternal deaths attributable to MiP in Madhya Pradesh

                Study year & reference

                Prevalence of MiP

                MiP cases per year1

                Fetal loss attributable to MiP2

                Maternal Deaths attributable to MiP3

                Ahmed et al (2007) [15]





                Singh et al (2005) [16]

                11–14% *




                Singh et al (1999)






                Korenramp et al (2004) [5]





                Singh et al (1998) [18]





                Singh et al (2001) [19]





                *MiP is defined as placental malaria

                1MiP cases = (number of births * 1.25 *prevalence of MiP)

                2 Fetal loss attributable to MiP = (MiP cases * fetal loss rate attributable to MiP) [20]

                3Maternal deaths associated with to MiP = (MiP cases * Case fatality rate of MiP) [20]

                Table 4

                Ranges of values of variables used in Berkeley Madonna Model*


                Lowest Value

                Highest Value

                MiP Prevalence



                MiP Stillbirth rate



                MiP Spontaneous abortion



                MiP Case Fatality Rate



                * Ranges based on values found in the literature and applied to the Berkeley Madonna Model

                Table 5

                Output from Monte Carlo simulation using Berkeley Madonna Model*



                Spontaneous Abortions


                Maternal Deaths






                Lower quartile















                Upper Quartile





                *Berkeley Madonna Input

                Total rural population (TPop) = 74481000–15967145

                Crude birth rate (CBR) = random (0.0307, 0.04376)

                Live Births (B) = TPop*CBR

                y = proportion of pregnancies ending in spontaneous abortion (SA) + proportion of pregnancies ending in stillbirth (SB)

                Total pregnancies (TP) = B/(1-y)

                MiP = TP*PrevMiP

                MiPSB = MiP*MiPSBr

                MiPSA = MiP*MiPSAr

                SevereMiP = 0.05*MiP

                MiPMM = SevereMiP*MiPcase fatality rate

                PrevMiP = random (0.02, 0.14)

                MiPSAr = random (0.15, 0.6)

                MiPSBr = random (.04, 0.16)

                MiPMMr = random (0.042, 0.168)

                SB = random (0.02, 0.08)

                SA = random (0.075, 0.30)

                Figure 1

                Distribution of estimates of malaria in pregnancy cases, spontaneous abortions, still births and maternal deaths based on Monte Carlo Simulation: minimum, maximum, upper and lower quartiles, and median values of each outcome in 500 runs of the model.

                Past research has suggested that tribal populations, forest cover, and malaria incidence are strongly correlated [2, 22, 23]. A study by Biswas [24] in a tribal population in Madhya Pradesh found a crude birth rate of 43/1000 and stillbirth rate of 270/1000 in tribal populations, compared a birth rate of 31/1000 and stillbirth rate of 39/1000 in the general population. Sharma et al [22] found an API of 284/1,000 population per year in highly forested and 32/1,000 in less forested regions, and that 40% of Madhya Pradesh is highly forested. Given that exact population distribution within forested regions is not known, this analysis assumes that all tribal people live in the forests, and thereby the differential impact of malaria on tribal populations can be calculated (Table 6). The tribal populations, which constitute only 18% of the total population, appear to shoulder as much as 30% of the MiP burden in Madhya Pradesh.
                Table 6

                The burden of MiP in tribal and non-tribal populations, Madhya Pradesh, 2006


                Tribal Population

                Non-tribal Population

                Whole population of Madhya Pradesh

                Annual parasite Prevalence (API) [22]




                Population in 2006







                Number of pregnancies







                Number MiP cases








                The prevalence of MiP is poorly characterized, leading to a wide range of values in the literature and a consequent wide range in the estimates of MiP cases in Madhya Pradesh. As stillbirths, spontaneous abortions and maternal deaths are difficult to measure at a population level [25], the available data are unlikely to be accurate. The Berkeley Madonna model allows for these variations and performed a multifaceted sensitivity analysis. The estimates that occur the most frequently when the model was run many hundred times helped to narrow the width of potential ranges of the magnitude of each output. This model helped to elucidate the potential range of estimates incorporating all variables, but also the most likely level of burden given known estimates. The median values of 220,000 MiP cases (inter-quartile range (IQR): 136,000–305,000) and 95,800 lost foetuses (IQR: 56,800–147,600) are probably plausible estimates. Even with the fairly conservative estimates for case fatality rate attributable to MiP, the median estimate of 1,000 maternal deaths annually attributable to MiP (IQR: 650–1,600) is a huge burden in the state.

                These rates are much higher than current official estimates suggest, although lower than estimates in the literature since these studies were conducted in hospital settings and therefore unrepresentative of the state as a whole. The maternal mortality ratio in Madhya Pradesh is estimated to be between 540–700/100,000 live births [25], which translates into a total of 12,350 maternal deaths (if the lower estimate of 540/100,000 is used). This would mean that roughly 8% of maternal deaths in Madhya Pradesh may be associated with malaria. As another example, if the state-wide stillbirth rate is 39/1,000 births, then there would be an extrapolated 93,000 stillbirths annually in Madhya Pradesh as a whole. This model estimates a median number of 19,800 stillbirths due to MiP, which would suggest roughly 21% of stillbirths in this state are due to MiP. Both of these extrapolations suggest that large proportions of state-wise adverse pregnancy outcomes are associated with malaria. Given that both stillbirth and maternal mortality rates are difficult to measure in the general population, it is possible that the denominator state-wide number of stillbirths and maternal deaths is an underestimate. Therefore, the proportion due to MiP could actually be lower than the above percentages suggest. Regardless of the underlying denominator of adverse outcomes in the general population, this model suggests that malaria is a significant factor in foetal and maternal deaths in this region. It is also important to keep in mind that these results suggest correlation between MiP and adverse pregnancy outcomes, not necessarily causality.

                This analysis also highlights the importance of considering the heterogeneity of the burden of MiP within Madhya Pradesh. MiP in tribal women is disproportionately high due to higher birth rates and a greater malaria prevalence linked to forest residence. A large proportion of India's tribal populations live in central/central-eastern India [26] and a recent study found strong correlation between tribal populations, malaria incidence (especially P. falciparum) and forest cover [23]. Therefore, it is essential to look in depth at the tribal populations and local environmental conditions to understand fully the burden MiP and the means of controlling it in this population. Given that Madhya Pradesh has received attention due to its high foetal and maternal death rates, focusing on preventing and treating malaria might have significant benefits.

                Control strategies for MiP focus primarily on Africa because the evidence base for the interventions is from Africa. There is no reported evidence on the efficacy, effectiveness or cost effectiveness of control measures of MiP in India. Currently in India, chemoprophylaxis with chloroquine is recommended for pregnant women living in high risk areas with low drug resistance, and chloroquine plus proguanil in highly resistant areas [27]. Recently intermittent preventive treatment for pregnant women in high risk using two doses of sulphadoxine-pyrimethamine was recommended by the Indian Drug Policy Working Group [2]. A review of data on efficacy of anti-malarials throughout India found that the majority of studies reported more than a 25% failure rate for chloroquine against P. falciparum by day 28 post treatment [2]. Research in Madhya Pradesh suggested that 23% of malaria cases were resistant to chloroquine [7]. Given that there is a huge burden of MiP in Madhya Pradesh in general, and in the tribal population in particular, research into appropriate interventions to reduce the burden of MiP needs to be conducted.

                This paper has not addressed or modeled the impact of MiP on LBW, preterm delivery, and maternal anaemia in this population. Past research has suggested that in high transmission settings, malaria as much as doubles the risk of LBW and is responsible for an estimated 26% of maternal anaemia [28]. High and low transmission settings have been found to have comparable LBW and maternal anaemia rates, although, as this paper highlights, low-transmission settings have the added burdens of maternal death and foetal loss [29]. Therefore, although not explicitly modeled here, it can be posited that LWB and maternal anaemia rates would be similar in Madhya Pradesh as in other malarious areas, and is an added cause of concern. Not only is MiP a pressing health concern today, but the importance of MiP will only continue to grow in India due to the combined threat of population growth and climate change [4]. More research is needed to pinpoint the number of women at risk, the most vulnerable among these women, and how to better protect them with appropriate treatment and prevention both today and in the future.

                The data presented in this paper, though not providing precise estimates of MiP in Madhya Pradesh, show the potential magnitude of cases of MiP, as well as malaria related foetal and maternal loss. This is the first step towards sensitizing the research community and advocating that sponsors of research build the evidence base on the burden of MiP in India so as to better evaluate potential interventions.



                The authors would like to thank Dr. S. Sharma, Dr. Rukhsana Ahmed, and Dr. R. M. Rastogi for their insights and support of this project.

                Authors’ Affiliations

                London School of Hygiene and Tropical Medicine
                Regional Malaria Research Centre for Tribals
                National Vector Borne Disease Control Programme
                National Institute for Malaria Reseach
                South East Asia Regional Office, World Health Organization


                1. Duffy P, Fried M: Malaria in Pregnancy: Deadly Parasite, Susceptible Host London; New York: Taylor and Francis 2001.View Article
                2. National Vector Borne Disease Control Programme: Joint Monitoring Mission Report National Vector Bourne Disease Control Programme: New Delhi, India 2007.
                3. Bhattacharya, Sharma C, Dhiman RC, Mitra AP: Climate change and malaria in India. Current Science 2006, 90: 369–375.
                4. Hay S, Guerra C, Tatem A, Noor A, Snow R: The global distribution and population at risk of malaria: past, present and future. Lancet Infect Dis 2004, 4: 327–336.View ArticlePubMed
                5. Korenromp E: Malaria Incidence Estimates at Country Level for the Year 2004. World Health Organization, Roll Back Malaria 2005.
                6. Matta S, Khokhar A, Sachdev TR: Assessment of knowledge about malaria among patients reported with fever: a hospital based study. Journal of Vector Borne Disease 2004, 41: 27–31.
                7. Singh N, Mishra AK, Shukla MM, Chand SK: Forest Malaria in Chhindwara, Madhya Pradesh, Central India: a case study in a tribal community. American Journal of Tropical Medical Hygiene 2003, 68 (5) : 602–607.
                8. Berkeley Madonna 2007.
                9. Guilmoto CZ, Rajan SI: District level estimates of Fertility from India's 2001 Census. Economic and Political Weekly 2002, 665–672.
                10. Government of India: Census of India 2001.
                11. Stanton C, Lawn J, Rahman H, Wilczynska-Ketende K, Hill K: Stillbirth rates: delivering estimates in 190 countries. The Lancet 2006, 367: 1487–1494.View Article
                12. World Health Organization: [http://​www.​who.​int/​whr/​2005/​annexes-en.​pdf] The World Health Report 2005.
                13. Curtis C: Meeting Health Care Needs of Women Experiencing Complications of Miscarriage and Unsafe Abortion: USAID's Postabortion Care Program. Journal of Midwifery and Women's Health 2007, 52: 368–375.View ArticlePubMed
                14. Das Gupta RK: Epidemiological Situation Report of Madhya Pradesh up to December 2006. (Edited by: Chandramohan D, Diamond-Smith N). 2007.
                15. Ahmed REA: Rapid Assessment of the burden of malaria in pregnancy in Madhya Pradesh, India: 025–39. Tropical Medicine and International Health 2007, (Supplement 12 1) : 46.
                16. Singh N, Saxena A, Awadhia SB, Shrivastavar R, Singh MP: Evaluation of a rapid diagnostic test for assessing the burden of malaria at delivery in India. Am J Trop Med Hyg 2005, 73 (5) : 855–858.PubMed
                17. Singh N, Shukla MM, Sharma VP: Epidemiology of malaria in pregnancy in central India. Bull World Health Organ 1999, 77 (7) : 567–572.PubMed
                18. Singh N, Saxena A, Chand SK, Valecha N, Sharma VP: Studies on malaria during pregnancy in a tribal area of central India (MP). The Southeastern Journal of Tropical Medicine and Public Health 1998., 29:
                19. Singh N, Mehra RK, Srivastava N: Malaria during pregnancy and infancy, in an area of intense malaria transmission in central India. Annals of Tropical Medicine and Parasitology 2001, 95 (1) : 19–29.View ArticlePubMed
                20. Konar H: Observations on Malaria in Pregnancy. Journal of Obstetrics and Gynaecology India 2004, 54 (5) : 456–59.
                21. Tagbor H, Bruce J, Browne E, Randal A, Greenwood B, Chandramohan D: Efficacy, safety, and tolerability of amodiaquine plus sulphadoxine-pyrimethamine used alone or in combination for malaria treatment in pregnancy: a randomised trial. The Lancet 2006, 368 (9544) : 1349–1356.View Article
                22. Sharma SK, Tyagi PK, Padhan K, Upadhyay AK, Haque MA, Nanda N, Joshi H, Biswas S, Adak T, Das BS, Chauhan VS, Chitnis CE, Subbarao SK: Epidemiology of malaria transmission in forest and plain ecotype villages of Sundargarh District Orissa, India. Transactions of the Royal Society of Tropical Medicine and Hygiene 2006, 100: 917–925.View ArticlePubMed
                23. Srivastava A: Cost effective malaria control strategy for Madhya Pradesh, India: a GIS based approach. Tropical Medicine and International Health 2007., (Supp 12) :
                24. Biswas RKKAK: Fertility Profile of a primitive tribe, Madhya Pradesh. Anthropologist 2003, 5 (3) : 161–167.
                25. Bhat PNM: Maternal Mortality in India: An update. Studies in Family Planning 2002, 33 (3) : 227–236.View ArticlePubMed
                26. Balgir RS: Do Tribal Communities show an inverse relationship between sickle cell disorders and glucose-6-phosphate dehydrogenase deficiency in malaria endemic areas of Central-Eastern India? Journal of Comparative Human Biology 2006, 57: 163–176.View ArticlePubMed
                27. Directorate of National Vector Borne Disease Control Programme: National Drug Policy M.o.H.a.F. Welfare, New Delhi, India 2007.
                28. Luxemburger C, McGready R, Kham1 A, Morison L, Cho T, Chongsuphajaisiddhi T, White NJ, Nosten F: Effects of Malaria During Pregnancy on Infant Mortality in an Area of Low Malaria Transmission. American Journal of Epidemiology 2001, 154 (5) : 459–465.View ArticlePubMed
                29. Desai M, Kuile FT, Nosten F, McGready R, Asamoa K, Brabin B, Newmanal R: Epidemiology and burden of malaria in pregnancy. Lancet Infectious Disease 2007, 7: 93–104.View Article


                © Diamond-Smith et al. 2009

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.