Malaria in pregnancy and the endemicity spectrum: what can we learn?

The increased susceptibility of pregnant women to malaria infection has long been recognized, but the magnitude of the disease burden in this particular group, together with the pathophysiology of maternal malaria and the specific difficulties in treatment, have only recently been the focus of research. Most research on maternal malaria has derived from sub-Saharan Africa where transmission is high, whereas most of the studies on the treatment of malaria and the effect of non-falciparum species has been conducted in low-transmission areas of Asia. In this paper, we attempt to improve our understanding of the disease and its mechanisms from observed differences and similarities between contrasting areas of transmission, and to identify priorities for future research.     

Thoughts on malaria in pregnancy with consideration of some factors which influence remedial strategies

There is evidence that pregnancy enhances the clinical severity of malaria, especially of P. falciparum infections. In pregnant women with little or no prior experience of the disease, P. falciparum causes severe clinical illness, substantial malaria mortality, increased rates of abortion and stillbirth and low birthweight of offspring; moreover, in such women, the clinical consequences seen unmodified by maternal parity. However, in pregnant women resident in highly endemic areas who have acquired considerable immunity through prolonged prior contact with malaria, parity appears to influence susceptibility to an important degree. Women who are pregnant for the first time are most affected, showing increased prevalence and density of parasitaemia, increased frequency of clinical illness (but not mortality) and significantly increased frequency of delivery of low birthweight children. In contrast, in multigravid women these clinical features are much less obvious and rarely attain statistical significance. The differences in susceptibility to malaria of pregnant women associated with parity and previous immunological experience require that protective strategies must be planned with full knowledge of the local epidemiology of malaria and be specifically targeted to the women who require them. Furthermore, the effectiveness of each strategy requires careful monitoring to permit such modifications as may be required by change in the immune status of the resident population.     

Impact of placental Plasmodium falciparum malaria on pregnancy and perinatal outcome in sub-Saharan Africa: I: introduction to placental malaria

Placental malaria is one of the major features of malaria during pregnancy and has been widely used as a standard indicator to characterize malaria infection in epidemiologic investigations. Although pathogenesis of placental malaria is only partially understood, placental sequestration of Plasmodium falciparum results in the accumulation of parasitized erythrocytes in the intervillous space, infiltration by inflammatory cells, and release of pro-inflammatory mediators, which cause pathologic alterations that could impair materno-fetal exchanges, often resulting in adverse pregnancy outcome. In this report, the impact of placental malaria on pregnancy and perinatal outcome is reviewed using data from studies conducted in sub-Saharan Africa. Generally, placental malaria was associated with increased risk of maternal anemia, HIV infection, and maternal mortality, with younger women and primigravidae more likely to be affected. A variety of adverse perinatal outcomes, including low birth weight, preterm delivery, intrauterine growth retardation, reduced fetal anthropometric parameters, fetal anemia, congenital malaria, increased mother-to-child HIV transmission, and perinatal mortality, were associated with placental malaria. There were, however, conflicting reports on whether the risk of these adverse perinatal outcomes associated with placental malaria were statistically significant. There is a clear need to strengthen the malaria prevention and intervention measures for pregnant women in sub-Saharan Africa.     

Malaria during pregnancy: a priority area of malaria research and control

More than 2000 million people live in areas where malaria transmission occurs and are therefore at risk of being infected. It follows that 1000 million people are exposed to the risks of malaria when pregnant. Although the special features of malaria during pregnancy have been recognized for nearly a century(1), it is only recently that it is being considered as a priority for malaria research and control, as discussed here by Clara Menendez.     

Impact of placental Plasmodium falciparum malaria on pregnancy and perinatal outcome in sub-Saharan Africa: II: effects of placental malaria on perinatal outcome; malaria and HIV

Placental malaria is recognized as a common complication of malaria in pregnancy in areas of stable transmission, and, as a consequence, serious health problems arise for the mother and especially her baby [1]. Although malaria in pregnancy is a major factor associated with adverse perinatal outcome, the link between malaria and perinatal morbidity/mortality is less clear in areas with stable endemic malaria where pregnant women have acquired immunity [2]. Histological examination of the placenta is a predictor of fetal morbidity, as well as being the most sensitive detector of maternal infection [3]. Adverse perinatal outcome has been described as an important indicator of poor quality of obstetric care and social development [4]. A variety of adverse perinatal outcomes associated with placental malaria have been described, including low birth weight, preterm delivery, intrauterine growth retardation, fetal anemia, congenital malaria, and fetal mortality. The most common clinical features in 80 percent of perinatal cases are fever, anemia, and splenomegaly [5]. Other signs and symptoms include hepatomegaly, jaundice, regurgitation, loose stools, poor feeding, and, occasionally, drowsiness, restlessness, and cyanosis also can be seen [5,6].A review of studies that investigated these poor fetal outcomes associated with placental malaria in sub-Saharan Africa is presented here.     

Transmission of Plasmodium vivax in south-western Uganda: report of three cases in pregnant women

Plasmodium vivax is considered to be rare in the predominantly Duffy negative populations of Sub-Saharan Africa, as this red blood cell surface antigen is essential for invasion by the parasite. However, despite only very few reports of molecularly confirmed P. vivax from tropical Africa, serological evidence indicated that 13% of the persons sampled in Congo had been exposed to P. vivax. We identified P. vivax by microscopy in 8 smears from Ugandan pregnant women who had been enrolled in a longitudinal study of malaria in pregnancy. A nested polymerase chain reaction (PCR) protocol was used to detect and identify the Plasmodium parasites present. PCR analysis confirmed the presence of P. vivax for three of the women and analysis of all available samples from these women revealed clinically silent chronic low-grade vivax infections for two of them. The parasites in one woman carried pyrimethamine resistance-associated double non-synonymous mutations in the P. vivax dihydrofolate reductase gene. The three women found infected with P. vivax were Duffy positive as were nine of 68 women randomly selected from the cohort. The data presented from these three case reports is consistent with stable transmission of malaria in a predominantly Duffy negative African population. Given the substantial morbidity associated with vivax infection in non-African endemic areas, it will be important to investigate whether the distribution and prevalence of P. vivax have been underestimated in Sub-Saharan Africa. This is particularly important in the context of the drive to eliminate malaria and its morbidity.     

Treatment-seeking practices for malaria in pregnancy among rural women in Mukono district, Uganda

Understanding treatment-seeking practices for malaria in pregnancy is necessary in designing effective programmes to address the high malaria morbidity in pregnancy. This study assessed women's perceptions on malaria in pregnancy, recognition of early signs of pregnancy and of malaria, and the cultural context in which treatment seeking takes place in Mukono District. Focus group discussions (FGD) and key informant interviews were conducted among pregnant women, non-pregnant women, adolescents and men. The results showed that malaria, locally known as omusujja, was perceived as the most common cause of ill health among pregnant women. Although malaria commonly presents with fever, some pregnant women feel hot in the womb with or without signs of fever and this illness, locally known as nabuguma, may lead to progressive weakness and occasionally to miscarriage and few respondents associated it with malaria. Primigravidae, adolescents and men were not considered at risk of omusujja or nabuguma. Similarly anaemia and low birth weight were not associated with malaria; in fact paleness was described as a normal sign of pregnancy. There are cultural and social pressures on married women to get pregnant and this forces them to conceal symptoms like feeling feverishness, backache, nausea, general weakness, loss of appetite and vomiting until they are sure these are due to pregnancy. Most women, however, could not differentiate symptoms of malaria from those of early pregnancy. There is a belief that omusujja is a normal sign of pregnancy and this is coupled with a strong cultural practice of using herbs and clays as a first resort to treat pregnancy ailments including malaria. The cultural beliefs and practices regarding delivery of twin and first births, coupled with the high cost of care, prevent women from delivering and using other services at health units.     

A decade of malaria during pregnancy in Brazil: what has been done concerning prevention and management

In Brazil, malaria remains a disease of major epidemiological importance because of the high number of cases in the Amazonian Region. Plasmodium spp infections during pregnancy are a significant public health problem with substantial risks for the pregnant woman, the foetus and the newborn child. In Brazil, the control of malaria during pregnancy is primarily achieved by prompt and effective treatment of the acute episodes. Thus, to assure rapid diagnosis and treatment for pregnant women with malaria, one of the recommended strategy for low transmission areas by World Health Organization and as part of a strategy by the Ministry of Health, the National Malaria Control Program has focused on integrative measures with woman and reproductive health. Here, we discuss the approach for the prevention and management of malaria during pregnancy in Brazil over the last 10 years (2003-2012) using morbidity data from Malaria Health Information System. Improving the efficiency and quality of healthcare and education and the consolidation of prevention programmes will be challenges in the control of malaria during pregnancy in the next decade.     

Asymptomatic Plasmodium falciparum Malaria in Pregnant Women in the Chittagong Hill Districts of Bangladesh

Background

Pregnancy is a known risk factor for malaria which is associated with increased maternal and infant mortality and morbidity in areas of moderate-high malaria transmission intensity where Plasmodium falciparum predominates. The nature and impact of malaria, however, is not well understood in pregnant women residing in areas of low, unstable malaria transmission where P. falciparum and P. vivax co-exist.

Methods

A large longitudinal active surveillance study of malaria was conducted in the Chittagong Hill Districts of Bangladesh. Over 32 months in 2010–2013, the period prevalence of asymptomatic P. falciparum infections was assessed by rapid diagnostic test and blood smear and compared among men, non-pregnant women and pregnant women. A subset of samples was tested for infection by PCR. Hemoglobin was assessed. Independent risk factors for malaria infection were determined using a multivariate logistic regression model.

Results

Total of 34 asymptomatic P. falciparum infections were detected by RDT/smear from 3,110 tests. The period prevalence of asymptomatic P. falciparum infection in pregnant women was 2.3%, compared to 0.5% in non-pregnant women and 0.9% in men. All RDT/smear positive samples that were tested by PCR were PCR-positive, and PCR detected additional 35 infections that were RDT/smear negative. In a multivariate logistic regression analysis, pregnant women had 5.4-fold higher odds of infection as compared to non-pregnant women. Malaria-positive pregnant women, though asymptomatic, had statistically lower hemoglobin than those without malaria or pregnancy. Asymptomatic malaria was found to be evenly distributed across space and time, in contrast to symptomatic infections which tend to cluster.

Conclusion

Pregnancy is a risk factor for asymptomatic P. falciparum infection in the Chittagong Hill Districts of Bangladesh, and pregnancy and malaria interact to heighten the effect of each on hemoglobin. The even distribution of asymptomatic malaria, without temporal and spatial clustering, may have critical implications for malaria elimination strategies.     

Malaria in the Post-Partum Period; a Prospective Cohort Study

Background

Several studies have shown a prolonged or increased susceptibility to malaria in the post-partum period. A matched cohort study was conducted to evaluate prospectively the susceptibility to malaria of post-partum women in an area where P.falciparum and P.vivax are prevalent.

Methods

In an area of low seasonal malaria transmission on the Thai-Myanmar border pregnant women attending antenatal clinics were matched to a non-pregnant, non-post-partum control and followed up prospectively until 12 weeks after delivery.

Results

Post-partum women (n = 744) experienced significantly less P.falciparum episodes than controls (hazard ratio (HR) 0.39 (95%CI 0.21–0.72) p = 0.003) but significantly more P.vivax (HR 1.34 (1.05–1.72) p = 0.018). The reduced risk of falciparum malaria was accounted for by reduced exposure, whereas a history of P.vivax infection during pregnancy was a strong risk factor for P.vivax in post-partum women (HR 13.98 (9.13–21.41), p<0.001). After controlling for effect modification by history of P.vivax, post-partum women were not more susceptible to P.vivax than controls (HR: 0.33 (0.21–0.51), p<0.001). Genotyping of pre-and post-partum infections (n⊕ = ⊕10) showed that each post-partum P.falciparum was a newly acquired infection.

Conclusions

In this area of low seasonal malaria transmission post-partum women were less likely to develop falciparum malaria but more likely to develop vivax malaria than controls. This was explained by reduced risk of exposure and increased risk of relapse, respectively. There was no evidence for altered susceptibility to malaria in the post-partum period. The treatment of vivax malaria during and immediately after pregnancy needs to be improved.     

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

Background

Comprehensive and contemporary estimates of the number of pregnancies at risk of malaria are not currently available, particularly for endemic areas outside of Africa. We derived global estimates of the number of women who became pregnant in 2007 in areas with Plasmodium falciparum and P. vivax transmission.

Methods and Findings

A recently published map of the global limits of P. falciparum transmission and an updated map of the limits of P. vivax transmission were combined with gridded population data and growth rates to estimate total populations at risk of malaria in 2007. Country-specific demographic data from the United Nations on age, sex, and total fertility rates were used to estimate the number of women of child-bearing age and the annual rate of live births. Subregional estimates of the number of induced abortions and country-specific stillbirths rates were obtained from recently published reviews. The number of miscarriages was estimated from the number of live births and corrected for induced abortion rates. The number of clinically recognised pregnancies at risk was then calculated as the sum of the number of live births, induced abortions, spontaneous miscarriages, and stillbirths among the population at risk in 2007. In 2007, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission resulting in 82.6 million live births. This included 77.4, 30.3, 13.1, and 4.3 million pregnancies in the countries falling under the World Health Organization (WHO) regional offices for South-East-Asia (SEARO) and the Western-Pacific (WPRO) combined, Africa (AFRO), Europe and the Eastern Mediterranean (EURO/EMRO), and the Americas (AMRO), respectively. Of 85.3 million pregnancies in areas with P. falciparum transmission, 54.7 million occurred in areas with stable transmission and 30.6 million in areas with unstable transmission (clinical incidence <1 per 10,000 population/year); 92.9 million occurred in areas with P. vivax transmission, 53.0 million of which occurred in areas in which P. falciparum and P. vivax co-exist and 39.9 million in temperate regions with P. vivax transmission only.

Conclusions

In 2007, 54.7 million pregnancies occurred in areas with stable P. falciparum malaria and a further 70.5 million in areas with exceptionally low malaria transmission or with P. vivax only. These represent the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria and provide a first step towards a more informed estimate of the geographical distribution of infection rates and the corresponding disease burden of malaria in pregnancy. Please see later in the article for the Editors'' Summary     

Pregnancy-associated malaria: parasite binding, natural immunity and vaccine development

Humans living in areas of high malaria transmission gradually acquire, during the early years of life, protective clinical immunity to Plasmodium falciparum, limiting serious complications of malaria to young children. However, pregnant women become more susceptible to severe P. falciparum infections during their first pregnancy. Pregnancy associated malaria is coupled with massive accumulation of parasitised erythrocytes and monocytes in the placental intervillous blood spaces, contributing to disease and death in pregnant women and developing infants. Indirect evidence suggests that prevention may be possible by vaccinating women of childbearing age before their first pregnancy. This review aims to introduce the reader to the implications of malaria infection during pregnancy and to analyse recent findings towards the identification and characterisation of parasite encoded erythrocyte surface proteins expressed in malaria-infected pregnant women that are likely targets of protective immunity and have potential for vaccine development.     

High avidity antibodies to full-length VAR2CSA correlate with absence of placental malaria

VAR2CSA mediates sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, increasing the risk of poor pregnancy outcomes. Naturally acquired antibodies (Ab) to placental parasites at delivery have been associated with improved pregnancy outcomes, but Ab levels and how early in pregnancy Ab must be present in order to eliminate placental parasites before delivery remains unknown. Antibodies to individual Duffy-binding like domains of VAR2CSA have been studied, but the domains lack many of the conformational epitopes present in full-length VAR2CSA (FV2). Thus, the purpose of this study was to describe the acquisition of Ab to FV2 in women residing in high and low transmission areas and determine how Ab levels during pregnancy correlate with clearance of placental parasites. Plasma samples collected monthly throughout pregnancy from pregnant women living in high and low transmission areas in Cameroon were evaluated for Ab to FV2 and the proportion of high avidity Ab (i.e., Ab that remain bound in the presence of 3M NH(4)SCN) was assessed. Ab levels and proportion of high avidity Ab were compared between women with placental malaria (PM(+)) and those without (PM(-)) at delivery. Results showed that PM(-) women had significantly higher Ab levels (p = 0.0047) and proportion of high avidity Ab (p = 0.0009) than PM(+) women throughout pregnancy. Specifically, women with moderate to high Ab levels (>5,000 MFI) and those with ≥ 35% high avidity Ab at 5-6 months were found to have 2.3 (95% CI, 1.0-4.9) and 7.6-fold (p = 0.0013, 95% CI: 1.2-50.0) reduced risk of placental malaria, respectively. These data show that high levels of Ab to FV2, particularly those with high avidity for FV2, produced by mid-pregnancy are important in clearing parasites from the placenta. Both high Ab levels and proportion of high avidity Ab to FV2 may serve as correlates of protection for assessing immunity against placental malaria.     

Impact of irrigation on malaria in Africa: paddies paradox

The high population growth rate of the African continent has led to an increased demand for food and is in danger of outstripping agricultural production. In order to meet this need, many governments have sought ways of improving food production by initiating large-scale irrigation projects, involving reclamation of arid and semi-arid areas for the cultivation of crops. Although crop irrigation promises one solution to alleviating hunger and encourages economic growth, irrigation has often been blamed for aggravating disease in local communities. Malaria is one of the major tropical diseases associated with irrigation schemes, and changes in the transmission pattern of this disease following irrigation development have been a perennial subject of debate. It has often been assumed that high numbers of malaria vector Anopheles mosquitoes (Diptera: Culicidae) resulting from irrigation schemes lead inevitably to increased malaria in local communities. However, recent studies in Africa have revealed a more complex picture. Increased numbers of vectors following irrigation can lead to increased malaria in areas of unstable transmission, where people have little or no immunity to malaria parasites, such as the African highlands and desert fringes. But for most of sub-Saharan Africa, where malaria is stable, the introduction of crop irrigation has little impact on malaria transmission. Indeed, there is growing evidence that for many sites there is less malaria in irrigated communities than surrounding areas. The explanation for this finding is still unresolved but, in some cases at least, can be attributed to displacement of the most endophilic and anthropophilic malaria vector Anopheles funestus Giles by An. arabiensis Patton with lower vectorial capacity, as the latter thrives more than the former in ricefields. Similarly, among members of the An. gambiae complex, some cytotypes of An. gambiae sensu stricto are more vectorial than others. For example, the Mopti form has high vectorial capacity and breeds perennially in irrigated sites, whereas the savanna form is often sympatric but more seasonal. Also we suggest that many communities near irrigation schemes benefit from the greater wealth created by these schemes. Consequently irrigation communities often have greater use of bednets, better access to improved healthcare and receive fewer infective bites compared with those outside such development schemes. Thus, in most cases, irrigation schemes in Africa do not appear to increase malaria risk, except in areas of unstable transmission. However, developers should take the opportunity to improve health-care facilities for local communities when planning irrigation schemes wherever they occur.     

Effects of artemisinins on reticulocyte count and relationship to possible embryotoxicity in confirmed and unconfirmed malarial patients

Rat studies suggest that artemisinin-induced decreases in reticulocyte count are a marker for embryotoxicity (in one study, r = 0.82; p < 0.05). In clinical studies, therapeutic doses of artemisinins induced decreases in reticulocyte count that were larger in five of six groups of healthy volunteers (mean decreases of 47-75%) than in 12 groups of patients with malaria (mean decreases of 0-34% and incidences of low reticulocyte count of 0.6-18%). Malaria causes hypoferremia and drug concentrates in infected red cells so, among the explanations for the lesser decreases in patients, is that malaria protects against artemisinin-induced decreases in reticulocyte count by reducing the target tissue levels of active drug and/or ferrous iron which activates the drug to toxic free radicals. The disease could also protect against embryotoxicity in which case pregnant women without malaria would be at greater risk of artemisinin-induced embryotoxicity. Malaria protection against artesunate toxicity has been observed in rats. No artemisinin-induced embryotoxicity has been identified in limited numbers of women with confirmed malaria in the first trimester. However, in large parts of tropical Africa, malaria treatment is based on fever rather than confirmation of parasitemia and many pregnant women without malaria are exposed to antimalarials. No clinical studies have been conducted on uninfected women for whom pregnancy was identified and then an artemisinin was administered subsequently. Testing in rats and/or humans is needed to determine if malaria protects against reticulocytopenia and embryotoxicity and whether the parasite is a more or less sensitive target than the embryo and reticulocyte.     

Anti-malarial drugs and the prevention of malaria in the population of malaria endemic areas

Anti-malarial drugs can make a significant contribution to the control of malaria in endemic areas when used for prevention as well as for treatment. Chemoprophylaxis is effective in preventing deaths and morbidity from malaria, but it is difficult to sustain for prolonged periods, may interfere with the development of naturally acquired immunity and will facilitate the emergence and spread of drug resistant strains if applied to a whole community. However, chemoprophylaxis targeted to groups at high risk, such as pregnant women, or to periods of the year when the risk from malaria is greatest, can be an effective and cost effective malaria control tool and has fewer drawbacks. Intermittent preventive treatment, which involves administration of anti-malarials at fixed time points, usually when a subject is already in contact with the health services, for example attendance at an antenatal or vaccination clinic, is less demanding of resources than chemoprophylaxis and is now recommended for the prevention of malaria in pregnant women and infants resident in areas with medium or high levels of malaria transmission. Intermittent preventive treatment in older children, probably equivalent to targeted chemoprophylaxis, is also highly effective but requires the establishment of a specific delivery system. Recent studies have shown that community volunteers can effectively fill this role. Mass drug administration probably has little role to play in control of mortality and morbidity from malaria but may have an important role in the final stages of an elimination campaign.     

Combating malaria in Africa

The spread of antimalarial drug resistance has major consequences for malaria control in tropical Africa. Here, the impact of chloroquine resistance on the burden of malaria is analyzed and its implications for the Roll Back Malaria initiative are examined. Malaria mortality has increased at least twofold during the past two decades. Combination therapy should be available for home treatment of young children. The potential toxicity of most antimalarials will require special surveillance programs. The main contribution to malaria control using methods to reduce the entomological inoculation rate is expected in areas with low or unstable transmission. Classic vector-control methods could potentially eliminate malaria in most urban areas and such programs deserve high priority.     

Prevalence and risk factors for Plasmodium falciparum malaria in pregnant women of eastern Sudan

Background

Pregnant women are more susceptible to malaria, which is associated with serious adverse effects on pregnancy. The presentation of malaria during pregnancy varies according to the level of transmission in the area. Our study aimed to demonstrate the prevalence and risk factors for malaria (age, parity and gestational age) among pregnant women of eastern Sudan, which is characterized by unstable malaria transmission.

Methods

The prevalence and possible risk factors for Plasmodium falciparum malaria were investigated in 744 pregnant Sudanese women attending the antenatal clinic of New Haifa Teaching Hospital, eastern Sudan, during October 2003-April 2004.

Results

A total 102 (13.7%) had P. falciparum malaria, 18(17.6%) of these were severe cases (jaundice and severe anaemia). Univariate and multivariate analysis showed that, age and parity were not associated with malaria. Women who attended the antenatal clinic in the third trimester were at highest risk for malaria (OR = 1.58, 95% CI = 1.02–2.4; P < 0.05). Women with malaria had significantly lower mean haemoglobin (9.4 g/dl, 95% CI 9.1–9.7 versus 10.7, CI 10.6–10.8, P < 0.05). A significantly lower haemoglobin was observed in those with severe falciparum malaria compared to non-severe form (8.3 g/dl, 95% CI 7.6–9.1 versus 9.4, 95% CI 9.1–9.7, P = < 0.05).

Conclusion

The results suggest that P. falciparum malaria is common in pregnant women attending antenatal care and that anaemia is an important complication. Preventive measures (chemoprophylaxis and insecticide-treated bednets) may be beneficial in this area for all women irrespective of age or parity.