Version May 2024
INTRODUCTION — Malaria infection in pregnancy is a major cause of maternal death, maternal anemia, and adverse pregnancy outcome (spontaneous abortion, preterm delivery, growth restriction/low birth weight, stillbirth, congenital infection, neonatal mortality) in geographic areas where malaria infection occurs commonly in pregnant women [1]. Pregnancy increases the chances of developing malaria infection and severe disease when infected. Pregnant women are particularly vulnerable to Plasmodium falciparum infection because red cells infected with the parasite can sequester in the placenta, and thereby cause adverse fetal effects. If anti-malarial drugs do not achieve therapeutic levels in the placenta, parasites sequestered there may be released intermittently into the peripheral blood and cause recurrent maternal infection [2].
Issues related to the epidemiology, clinical manifestations, diagnosis, and outcome of malaria in pregnancy will be reviewed here. Issues related to prevention and treatment of malaria in pregnancy are discussed separately. (See "Malaria in pregnancy: Prevention and treatment" and "Treatment of severe malaria", section on 'Pregnancy'.)
General issues related to malaria are also discussed separately:
●(See "Malaria: Epidemiology, prevention, and control".)
●(See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)
●(See "Laboratory tools for diagnosis of malaria".)
●(See "Prevention of malaria infection in travelers".)
●(See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)
●(See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)
●(See "Non-falciparum malaria: Plasmodium knowlesi".)
EPIDEMIOLOGY — Malaria occurs in most tropical countries [3]. Epidemiology within a region may vary considerably depending on location (eg, rural versus city), season (rainy versus dry), human migration patterns, and use of malaria prevention strategies. The risk of locally acquired malaria is extremely low in the United States, but rare cases were identified in 2023 [4]. (See "Malaria: Epidemiology, prevention, and control".)
In general, for women living in a given geographic area, a higher prevalence of malaria has been observed among pregnant women than nonpregnant women, younger pregnant women than older pregnant women, women in their first or second pregnancies than in more multigravid women, human immunodeficiency virus (HIV)-infected women than women without HIV infection, and women in the first and second trimesters than women in the third trimester [5-8].
The increased prevalence of malaria in pregnant women has been attributed to multiple factors, including increased susceptibility to mosquito bites [9,10], immunologic and hormonal changes related to pregnancy, and the ability of infected erythrocytes to adhere to and sequester in the intervillous space (ie, the vascular space filled with maternal blood on the maternal side of the placenta) [11,12] (see 'Pathogenesis' below). The increased risk for acquiring malaria and developing more severe disease persists for at least 60 to 70 days postpartum [13,14].
In sub-Saharan Africa (a high transmission region), the median prevalence of maternal malaria (defined as peripheral or placental infection identified by microscopy) is 28 percent [5]. The prevalence can be even higher when more sensitive diagnostic methods (such as placental histology or polymerase chain reaction) are used [5,15]. In low transmission regions such as Asia and Latin America, the reported median prevalence of maternal malaria was 6.2 percent in 2007 [5]; however, malaria transmission is declining in these regions, so current prevalence may be lower.
MICROBIOLOGY — Species of malaria in humans include P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. The effect of malaria on pregnancy varies by species and correlates with the ability of infected erythrocytes to adhere to and sequester in the placenta. (See 'Pathogenesis' below.)
●P. falciparum invades red cells of all ages; it is associated with especially high levels of parasitemia, placental sequestration, and severe adverse maternal-fetal sequelae.
●P. vivax is infrequently associated with placental sequestration and less commonly associated with severe adverse maternal and fetal outcomes [16-19].
●P. knowlesi is relatively rare in pregnancy, but severe disease in pregnant women has been described in Southeast Asia [20]. No placental changes have been observed in association with P. knowlesi infection [11].
●P. ovale and P. malariae are not typically associated with severe illness in pregnancy. No placental changes have been observed in association with P. ovale or P. malariae infection [11].
Coinfection with multiple species is relatively uncommon and varies in prevalence with transmission intensity; it is most frequently observed with P. falciparum and P. vivax [21]. Sequential infection with the same or different species occurs more commonly than coinfection.
Issues related to non-falciparum malaria species are discussed further separately. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)
PATHOLOGY
Placental infection — Parasites may be absent in the peripheral blood but present in the placenta. In one study of 415 patients in Tanzania with histologic evidence of active placental malaria infection, parasitemia was absent in 46 percent of cases [22].
In endemic settings, placental histology is largely a research tool, as it is only performed after delivery and cannot guide pregnancy management. Histopathologic findings of the malaria-infected placenta include [12]:
●Infected erythrocytes and increased numbers of maternal phagocytic cells, especially monocytes, in the intervillous space.
●Hemozoin (malaria pigment) deposition in phagocytic leucocytes and within fibrin deposits in the intervillous space.
●Trophozoite and schizont stages of the parasite.
●Syncytial degradation and increased syncytial knotting; in rare cases, localized destruction of the villi [23].
Pathogenesis — The key finding of P. falciparum malaria in pregnant women is parasites in the erythrocytes sequestered in the intervillous space (picture 1) [24]. These infected erythrocytes are immunologically distinct from infected erythrocytes found in nonpregnant individuals: they express a specific class of variant surface antigen (pregnancy-associated malaria variant surface antigen [VSA-PAM]) that mediates adhesion of infected erythrocytes to chondroitin sulfate A (CSA) on the syncytiotrophoblast lining the intervillous space [25,26]. VAR2CSA, which is the product of the parasite gene VAR2CSA, appears to be the major VSA-PAM involved, but additional VSA-PAMs may also exist [27-29].
Adherence of erythrocytes expressing VSA-PAMs to the surface of syncytiotrophoblast appears to stimulate an inflammatory response. This results in monocyte migration and release of humoral factors, such as tumor necrosis factor-alpha (TNF-alpha), into the intervillous circulation that may promote preterm labor [30]. The concentration of TNF-alpha in the intervillous circulation correlates with the density of P. falciparum-infected erythrocytes. Individuals who carry the TNF 2 polymorphism in the promoter region of the TNF-alpha gene have heightened TNF-alpha production in response to infection, which increases their risk of preterm delivery, severe infection, and cerebral malaria [30].
Other potential consequences of erythrocyte adherence include placental thickening and altered placental functions, including reduced nutrient transport and production of key hormones (eg, insulin-like growth factor 1) [31,32]. Together, these placental changes may reduce uteroplacental blood flow [33] and, early in pregnancy, may impede villous growth and development [34]. The resulting reduction in the fetal supply of oxygen, nutrients, and growth factors can lead to fetal growth restriction and fetal demise [33-41].
Antibodies formed in response to VSA-PAM (particularly anti-VAR2CSA) prevent adhesion of the infected erythrocyte to the placenta [42,43]. These antibodies are sex specific (ie, men from malaria-endemic areas do not develop VSA-PAM antibodies) and correlate directly with parity in holoendemic (high transmission) areas. Primigravid women in holoendemic areas have no or low VSA-PAM immunoglobulin G (IgG) levels despite lifelong P. falciparum exposure, and thus are more prone to complications of pregnancy-associated malaria (eg, low birth weight, preterm delivery, maternal anemia) compared with multigravid women in holoendemic areas, who have moderate-to-high VSA-PAM IgG levels.
By comparison, in mesoendemic (low transmission) areas and areas where malaria is promptly treated, multigravid women do not have moderate-to-high VSA-PAM IgG levels and remain at increased risk of complications of malaria in each pregnancy. As an example, when rates of malaria transmission, placental malaria, and peripheral parasitemia fell in Mozambique between 2003 and 2012, a parallel reduction occurred in levels of antimalarial IgG antibodies against both pregnancy-specific parasite lines (placental, or CSA-binding) and more general parasite lines [44]. As a result of this reduced immunity, pregnant women infected with malaria had a higher frequency of adverse pregnancy outcomes (lower maternal hemoglobin and newborn birth weight) than those with malaria in pregnancy prior to this period.
In contrast to the above discussion of P. falciparum, for women with P. vivax, a direct link between adverse outcome and placental changes and placental sequestration of infected erythrocytes has not been clearly demonstrated.
CLINICAL FINDINGS
General principles — The clinical presentation of malaria in pregnant women depends primarily on the endemicity of the region. Infection with more than one malaria species does not substantially alter clinical presentation. (See 'Epidemiology' above.)
●For women in holoendemic areas (high transmission rates), most malaria infections in pregnancy are asymptomatic, but the mother is at risk for developing anemia [45,46]. Maternal anemia and placental parasitemia may lead to adverse pregnancy outcomes, particularly low birth weight (which may represent intrauterine growth restriction or preterm birth or both). (See 'Pregnancy outcome' below.)
Primigravid women in holoendemic areas (who have no or low pregnancy-associated malaria variant surface antigen [VSA-PAM] IgG levels) are more prone to complications of pregnancy-associated malaria than multigravid women (who have moderate-to-high VSA-PAM IgG levels), as discussed above. (See 'Pathogenesis' above.)
●For women in mesoendemic areas (relatively low transmission rates) or for women returning to holoendemic areas after a prolonged absence, malaria infection is more likely to result in symptomatic illness and serious complications (eg, maternal anemia, adverse pregnancy outcome) than in women in holoendemic areas [5]. Gravidity tends not to be an important factor because of low immunity. (See 'Pregnancy outcome' below.)
●For women in areas of unstable malaria transmission (where there is little acquired immunity), both symptomatic illness and serious complications (eg, maternal anemia, miscarriage, stillbirth, low birth weight) are common when infection occurs. Gravidity tends not to be an important factor because of low immunity. (See 'Pregnancy outcome' below.)
The clinical manifestations of malaria are nonspecific and variable. Virtually all nonimmune individuals experience fever. Other frequent symptoms include chills, sweats, headache, myalgias, fatigue, nausea, abdominal pain, vomiting, diarrhea, jaundice, and cough. Hypoglycemia is a common complication of severe malaria, although the usual signs (sweating, tachycardia, neurologic impairment) are difficult to distinguish from systemic symptoms due to severe malaria. Compared with nonpregnant women, pregnant women experience more severe disease, including more hypoglycemia and more respiratory complications (pulmonary edema, acute respiratory distress syndrome) [47]. For example, hypoglycemia occurs in 58 percent of pregnant women [48] versus approximately 8 percent of nonpregnant adults [49]. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)
There is a semiquantitative relationship between the degree of parasitemia and severity of disease. In general, parasitemia is more prevalent in pregnant compared with nonpregnant women [35,50,51], with increased risk as early as the first trimester [52]. As an example, in a longitudinal study including more than 270 Beninese women followed from the preconception period through delivery, the incidence of microscopic and submicroscopic P. falciparum infections was highest in the first trimester [53].
Anemia is a common complication of malaria in pregnancy; approximately 60 percent of pregnant women presenting with malaria infection are anemic [54,55], and anemia may be one of the few signs of the disease [56]. The anemia is generally normocytic and normochromic, with a striking absence of reticulocytes. Microcytosis and hypochromia may be present due to the very high frequency of thalassemia trait and/or iron deficiency. Infected red cells may be seen on the peripheral blood smear. However, anemia can be due to one or more other etiologies, including nutritional deficiency or intestinal parasites (especially hookworm infections) in malaria-endemic settings. In one review, 5 to 10 percent of pregnant African women developed severe anemia (hemoglobin <7 to 8 g/dL), and one-quarter of these cases were attributed to malaria [5].
Women with HIV infection — Pregnant women with HIV infection are at increased risk for malaria acquisition, placental malaria, high parasite density, severe clinical disease, and maternal and neonatal mortality (relative to pregnant women without HIV infection) [7,57-62]. Among women with HIV infection, clinical outcomes for primigravid and multigravid women are comparable [61].
Malaria infection in patients with HIV infection has been associated with CD4 cell decline relative to patients with HIV infection without malaria [63]. Malaria infection may be associated with a temporary increase in HIV viral load, which returns to baseline after antimalarial treatment; it is uncertain whether this increase in viral load may be associated with an increase in risk of perinatal HIV transmission [7,62,64,65]. For this reason, if viral load is used to monitor the response to antiretroviral therapy, testing should be delayed for approximately two months if the patient has had a recent malaria infection.
DIAGNOSIS — Malaria should be suspected in the setting of fever (temperature ≥37.5°C) and relevant epidemiologic exposure (residence in or travel to an area where malaria is endemic).
The approach to diagnosis of malaria in pregnant women is the same as the approach in nonpregnant patients. (See "Laboratory tools for diagnosis of malaria".)
Low-density malaria infections that are detectable by polymerase chain reaction (PCR) but below the detection threshold of microscopy or rapid diagnostic tests (RDTs) can contribute to transmission. Submicroscopic infections can be common; in one study from Benin, the incidence of submicroscopic infection was almost double that of microscopic infections across all trimesters of pregnancy [53].
However, the clinical value of PCR to detect low-density malaria infection in pregnant women with negative microscopy or RDTs is uncertain, and there is insufficient evidence to warrant routine use of PCR for this purpose. PCR positive, microscopy negative infection detected in pregnant women was associated with poor infant outcomes in Benin [66]; however, this finding was not associated with poor outcomes in other regions such as Malawi [67], Ghana [68], or India [69].
Chorionic villus sampling is not used for prenatal diagnosis of placental malaria and theoretically could contribute to vertical transmission.
PREGNANCY OUTCOME
Overview — Adverse maternal and perinatal outcomes associated with P. falciparum or P. vivax malaria in pregnancy include [35,54,70-81]:
●Miscarriage
●Preterm birth (<37 weeks of gestation)
●Low birth weight (LBW; <2500 g at birth)
●Fetal growth restriction
●Stillbirth (intrauterine fetal demise)
●Neonatal mortality
●Congenital malaria infection
●Maternal anemia
●Maternal mortality
●Hypertensive disease of pregnancy
These complications are not mutually independent (eg, preterm birth often results in LBW) and do not occur with similar frequency in all infected women. Nonimmune women and women in regions of unstable transmission (who generally lack protective antibodies) are at increased risk of these outcomes when they develop malaria [5].
Women in areas with high stable transmission rates (who are likely to have developed protective antibodies) are less likely to experience adverse pregnancy outcomes when they develop malaria, although they remain at risk for anemia even if otherwise asymptomatic [82]. Within high transmission areas, young women and women of low parity are the subgroups most likely to experience an adverse pregnancy outcome because they are most likely to have absent or low protective antibody levels due to lower cumulative exposure to malaria over their lifetime and lower exposure to pregnancy-associated malaria variant surface antigens (VSA-PAMs) due to no or few previous pregnancies [27,54,82-90].
Fetal effects
Reduction in birth weight — In pregnancies complicated by malaria, both fetal growth restriction (estimated fetal weight <10th percentile for gestational age) and preterm birth (birth <37 weeks of gestation) contribute to LBW (<2500 g at birth) [33,91-95]. An increasing number of P. falciparum infections during a pregnancy increases the risk of LBW [96].
In some settings, malaria has been associated with up to 70 percent of fetal growth restriction and up to 25 percent of neonates with LBW [5]. Reduction in fetal weight and preterm birth occur primarily in infants of primigravidas, who are more likely to have severe placental sequestration, heavier parasite loads, anemia, and low levels of antibodies formed in response to VSA-PAM compared with multigravidas [27,35,46,50,97]. (See 'Pathogenesis' above.)
Maternal undernutrition, which is common in regions where malaria is prevalent, also plays a role. The effects of malnutrition and malaria infection on LBW appear to be independent, not synergistic [98].
Neurodevelopment — There is emerging evidence that maternal malaria infection may affect neurodevelopment [99-101]. In one study including 493 pregnant women in Benin with malaria infection whose children were followed to six years of age, children whose mothers had placental malaria and/or high-density peripheral blood infection were particularly likely to have impaired processing, cognitive, and learning capabilities [99].
Vertical transmission — All species of malaria parasite can be transmitted in utero; congenital disease is most often associated with P. falciparum and P. vivax. Placental infection is a prerequisite for, but does not predict, congenital disease. Placental infection is more common than cord blood parasitemia, which is more common than detection of parasites in the infant's peripheral blood [102].
Among immune pregnant women, the likelihood of transplacental malaria transmission appears to be small (up to 1.5 percent of cases) [103,104]. Semi-immune and nonimmune pregnant women have a much higher likelihood of transplacental malaria transmission (7 to 10 percent) [70,105,106].
Pregnant women with overt symptoms of malaria during pregnancy have a 1 to 4 percent risk of vertical transmission [107]. The low incidence of congenital infection despite the high incidence of placental infection is likely secondary to passive immunization via transplacental acquisition of maternal antibody [108].
Clinical manifestations of congenital malaria in newborns and prognosis are discussed separately. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children", section on 'Children versus adults'.)
Subsequent risk for malaria infection — Malaria infection during pregnancy may increase the subsequent risk of malaria infection in young children. In a meta-analysis of 11 studies, the pooled adjusted odds ratio for clinically defined malaria in young children was 2.82 (95% CI 1.82-4.38) [109]. The potential immunologic or epidemiologic factors underlying this association are subjects of ongoing study.
Maternal effects — Malaria is a leading cause of maternal mortality in regions of unstable endemicity where there are periodic epidemics among nonimmune patients [110]. Younger maternal age has been associated with higher rates of anemia and poorer maternal and fetal outcome, in part because younger women are more likely to be primigravid and nonimmune or only partially immune [6,54,111]. Maternal death may be related to cerebral malaria, acidosis, organ failure (pulmonary, renal, hepatic), and/or severe anemia.
The following studies are examples of the impact of malaria on maternal mortality in two countries:
●A study performed in The Gambia estimated that, during the malaria season, maternal mortality increased by 168 percent and the proportion of deaths due to anemia increased threefold [112]. It was estimated that malaria accounted for up to 93 maternal deaths per 100,000 live births.
●A review of pregnancy-related maternal deaths in an urban Mozambique setting identified 239 maternal deaths (320 maternal deaths/100,000 live births) [73]. In this series, 15.5 percent of the deaths were directly attributable to malaria, and 19.7 percent of the women who died were parasitemic with P. falciparum. Over one-third of the malaria-related deaths occurred in primigravid adolescents, primarily associated with severe anemia. Autopsies on 161 women showed that 44 (27.3 percent) had histologic evidence of splenic malarial infection.
●A subsequent prospective autopsy study including all consecutive pregnancy-related deaths in a tertiary level referral hospital in Mozambique noted massive accumulation of P. falciparum-infected erythrocytes in the small capillaries of the central nervous system, in most visceral capillaries (heart, lung, kidney, uterus), as well as the intervillous space [113].
PREVENTION AND TREATMENT — Prevention and treatment of malaria in pregnancy and management of pregnancy are discussed in detail separately. (See "Malaria in pregnancy: Prevention and treatment".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Malaria (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology
•Among women living in a geographic region, a higher prevalence of malaria has been observed among pregnant women than in nonpregnant women, younger pregnant women than older pregnant women, women in their first or second pregnancies than in more multigravid women, women with HIV infection than women without HIV infection, and women in the first and second trimesters than women in the third trimester. (See 'Epidemiology' above.)
•The increased prevalence of malaria in pregnant women has been attributed to multiple factors, including increased susceptibility to mosquito bites, immunologic and hormonal changes related to pregnancy, and the ability of infected erythrocytes to adhere to and sequester in the intervillous space. (See 'Epidemiology' above.)
●Pathophysiology
•In Plasmodium falciparum malaria, the infected erythrocytes (picture 1) are immunologically distinct from infected erythrocytes found in nonpregnant individuals: they express a specific class of variant surface antigen (pregnancy-associated malaria variant surface antigen [VSA-PAM]) that mediates adhesion of infected erythrocytes to chondroitin sulfate A (CSA) on the syncytiotrophoblast lining the intervillous space. VAR2CSA, which is the product of the parasite gene VAR2CSA, appears to be the major VSA-PAM involved. Once parasites adhere to the surface of trophoblastic villi, they induce an inflammatory response that may promote preterm labor. Another consequence is placental thickening from the inflammation, which may reduce placental transport of oxygen and nutrients, leading to fetal growth restriction and, possibly, fetal demise. (See 'Pathogenesis' above.)
•Antibodies formed in response to VSA-PAM (particularly anti-VAR2CSA) prevent cytoadhesion of the infected erythrocyte to the placenta; thus, primigravid women in holoendemic areas (who have no or low VSA-PAM IgG levels despite lifelong P. falciparum exposure) are more prone to complications of pregnancy-associated malaria than multigravid women in holoendemic areas, who have moderate-to-high VSA-PAM IgG levels. By comparison, in mesoendemic (low transmission) areas and areas where malaria is promptly treated, multigravid women do not have moderate-to-high VSA-PAM IgG levels and remain at increased risk of complications of malaria in each pregnancy. (See 'Pathogenesis' above.)
●Clinical findings
•The clinical presentation varies according to the endemicity of the region. For women in holoendemic (high transmission) areas, most malaria infections in pregnancy are asymptomatic, but the mother is at risk for developing anemia. For women in mesoendemic (relatively low transmission) areas or for women returning to holoendemic areas after a prolonged absence, malaria infection is more likely to result in symptomatic, and potentially life-threatening, illness and serious complications (eg, maternal anemia, adverse pregnancy outcome) than it is in women in holoendemic areas. For women in areas of unstable malaria transmission (where there is little acquired immunity), both symptomatic illness and serious complications (eg, maternal anemia, miscarriage, stillbirth, low birth weight) are common when infection occurs. (See 'Clinical findings' above.)
•Virtually all nonimmune individuals experience fever. Other frequent symptoms include chills, sweats, headache, myalgias, fatigue, nausea, abdominal pain, vomiting, diarrhea, jaundice, and cough, as well as symptoms of hypoglycemia. (See 'Clinical findings' above.)
●Diagnosis – Malaria should be suspected in the setting of fever (temperature ≥37.5°C) and relevant epidemiologic exposure (residence in or travel to an area where malaria is endemic). The approach to diagnosis of malaria in pregnant women is the same as the approach in nonpregnant patients. Peripheral blood smears are typically used for diagnosis but may be negative in women with placental malaria who are otherwise asymptomatic. (See 'Diagnosis' above and "Laboratory tools for diagnosis of malaria".)
●Pregnancy outcome – Adverse pregnancy outcomes associated with malaria include fetal growth restriction/small for gestational age infant, preterm birth, low birth weight, stillbirth and neonatal death, congenital malaria infection, and maternal mortality. (See 'Pregnancy outcome' above.)
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