Acquisition of antibodies to Plasmodium falciparum and Plasmodium vivax antigens in pregnant women living in a low malaria transmission area of Brazil.

BACKGROUND: Pregnant women have increased susceptibility to Plasmodium falciparum malaria and acquire protective antibodies over successive pregnancies. Most studies that investigated malaria antibody responses in pregnant women are from high transmission areas in sub-Saharan Africa, while reports from Latin America are scarce and inconsistent. The present study sought to explore the development of antibodies against P. falciparum and Plasmodium vivax antigens in pregnant women living in a low transmission area in the Brazilian Amazon. METHODS: In a prospective cohort study, plasma samples from 408 pregnant women (of whom 111 were infected with P. falciparum, 96 had infections with P. falciparum and P. vivax, and 201 had no Plasmodium infection) were used to measure antibody levels. Levels of IgG and opsonizing antibody to pregnancy-specific variant surface antigens (VSAs) on infected erythrocytes (IEs), 10 recombinant VAR2CSA Duffy binding like (DBL domains), 10 non-pregnancy-specific P. falciparum merozoite antigens, and 10 P. vivax antigens were measured by flow cytometry, ELISA, and multiplex assays. Antibody levels and seropositivity among the groups were compared. RESULTS: Antibodies to VSAs on P. falciparum IEs were generally low but were higher in currently infected women and women with multiple P. falciparum episodes over pregnancy. Many women (21%-69%) had antibodies against each individual VAR2CSA DBL domain, and antibodies to DBLs correlated with each other (r ≥ 0.55, p < 0.0001), but not with antibody to VSA or history of infection. Infection with either malaria species was associated with higher seropositivity rate for antibodies against P. vivax proteins, adjusted odds ratios (95% CI) ranged from 5.6 (3.2, 9.7), p < 0.0001 for PVDBPII-Sal1 to 15.7 (8.3, 29.7), p < 0.0001 for PvTRAg_2. CONCLUSIONS: Pregnant Brazilian women had low levels of antibodies to pregnancy-specific VSAs that increased with exposure. They frequently recognized both VAR2CSA DBL domains and P. vivax antigens, but only the latter varied with infection. Apparent antibody prevalence is highly dependent on the assay platform used.

Peripheral Plasmodium falciparum Infection in Early Pregnancy Is Associated With Increased Maternal Microchimerism in the Offspring.

BACKGROUND: Placental malaria has been associated with increased cord blood maternal microchimerism (MMc), which in turn may affect susceptibility to malaria in the offspring. We sought to determine the impact of maternal peripheral Plasmodium falciparum parasitemia during pregnancy on MMc and to determine whether maternal cells expand during primary parasitemia in the offspring. METHODS: We conducted a nested cohort study of maternal-infant pairs from a prior pregnancy malaria chemoprevention study. Maternal microchimerism was measured by quantitative polymerase chain reaction targeting a maternal-specific marker in genomic DNA from cord blood, first P falciparum parasitemia, and preparasitemia. Logistic and negative binomial regression were used to assess the impact of maternal peripheral parasitemia, symptomatic malaria, and placental malaria on cord blood MMc. Generalized estimating equations were used to assess predictors of MMc during infancy. RESULTS: Early maternal parasitemia was associated with increased detection of cord blood MMc (adjusted odds ratio = 3.91, P = .03), whereas late parasitemia, symptomatic malaria, and placental malaria were not. The first parasitemia episode in the infant was not associated with increased MMc relative to preparasitemia. CONCLUSIONS: Maternal parasitemia early in pregnancy may increase the amount of MMc acquired by the fetus. Future work should investigate the impact of this MMc on immune responses in the offspring.

Malaria Infection Is Common and Associated With Perinatal Mortality and Preterm Delivery Despite Widespread Use of Chemoprevention in Mali: An Observational Study 2010 to 2014.

BACKGROUND: In malaria-endemic areas, pregnant women and especially first-time mothers are more susceptible to Plasmodium falciparum. Malaria diagnosis is often missed during pregnancy, because many women with placental malaria remain asymptomatic or have submicroscopic parasitemia, masking the association between malaria and pregnancy outcomes. Severe maternal anemia and low birthweight deliveries are well-established sequelae, but few studies have confirmed the relationship between malaria infection and severe outcomes like perinatal mortality in high transmission zones. METHODS: Pregnant women of any gestational age enrolled at antenatal clinic into a longitudinal cohort study in Ouelessebougou, Mali, an area of high seasonal malaria transmission. Follow-up visits included scheduled and unscheduled visits throughout pregnancy. Blood smear microscopy and polymerase chain reaction (PCR) analysis were employed to detect both microscopic and submicroscopic infections, respectively. Intermittent preventative treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) was documented and prompt treatment regardless of symptoms given upon malaria diagnosis. RESULTS: Of the 1850 women followed through delivery, 72.6% of women received 2 or more IPTp-SP doses, 67.2% of women experienced at least 1 infection between enrollment up to and including delivery. Malaria infection increased the risks of stillbirth (adjusted hazard ratio [aHR] 3.87, 95% confidence interval [CI]: 1.18-12.71) and preterm delivery (aHR 2.41, 95% CI: 1.35-4.29) in primigravidae, and early neonatal death (death within 7 days) in secundigravidae and multigravidae (aHR 6.30, 95% CI: 1.41-28.15). CONCLUSIONS: Malaria treatment after diagnosis, alongside IPTp-SP, is insufficient to prevent malaria-related stillbirth, early neonatal death and preterm delivery (PTD). Although IPTp-SP was beneficial in Mali during the study period, new tools are needed to improve pregnancy outcomes. CLINICAL TRIALS REGISTRATION: NCT01168271.

Fetal and Maternal Innate Immunity Receptors Have Opposing Effects on the Severity of Experimental Malaria in Pregnancy: Beneficial Roles for Fetus-Derived Toll-Like Receptor 4 and Type I Interferon Receptor 1.

Malaria in pregnancy (MiP) is a distinctive clinical form of Plasmodium infection and is a cause of placental insufficiency leading to poor pregnancy outcomes. Maternal innate immunity responses play a decisive role in the development of placental inflammation, but the action of fetus-derived factors in MiP outcomes has been overlooked. We investigated the role of the Tlr4 and Ifnar1 genes, taking advantage of heterogenic mating strategies to dissect the effects mediated by maternally and fetally derived Toll-like receptor 4 (TLR4) or type I interferon receptor 1 (IFNAR1). Using a mouse infection system displaying severe MiP outcomes, we found that the expressions of TLR4 and IFNAR1 in the maternal compartment take part in deleterious MiP outcomes, but their fetal counterparts patently counteract these effects. We uncovered that fetal TLR4 contributes to the in vitro uptake of infected erythrocytes by trophoblasts and to the innate immune response in the placenta, offering robust protection of fetus viability, but had no sensible impact on the placental parasite burden. In contrast, we observed that the expression of IFNAR1 in the fetal compartment was associated with a reduced placental parasite burden but had little beneficial effect on fetus outcomes. Furthermore, the downregulation of Ifnar1 expression in infected placentas and in trophoblasts exposed to infected erythrocytes indicated that the interferon-IFNAR1 pathway is involved in the trophoblast response to infection. This work unravels that maternal and fetal counterparts of innate immune pathways drive opposing responses in murine placental malaria and implicates the activation of innate receptors in fetal trophoblast cells in the control of placental infection and in the protection of the fetus.

Usefulness of a biomarker to identify placental dysfunction in the context of malaria.

In most tropical areas, pregnant women are at increased risk of malaria, as a consequence of the massive sequestration of parasitized red blood cells in the placenta. The placenta plays a key role in embryonic and fetal development as well as in maternal-fetal exchanges, and pregnancy-associated malaria may alter selected placenta functions that lead to stillbirth and low birth weight. Although there are several tools (blood smear examination, RDT, PCR) to diagnose malaria infection during pregnancy, there is currently no test to assess placenta dysfunction in the framework of pregnancy-associated malaria. Pregnancy-associated malaria shares many features with preeclampsia, an extensively studied disease. Various biomarkers associated with placental dysfunction have been identified as associated with preeclampsia. Several of these are inflammatory markers that lack of specificity. A few seem more specific of placenta dysfunction, including s-endoglin and sFlt1, increased in the peripheral blood during preeclampsia. The predictive value of these biomarkers should be studied in the context of pregnancy-associated malaria to evaluate their usefulness in identifying placental dysfunction during malaria. These biomarkers should be considered to improve the diagnosis of placental dysfunction during malaria and pregnant women monitoring.

Malaria and Helminthic Co-Infection during Pregnancy in Sub-Saharan Africa: A Systematic Review and Meta-Analysis.

Malaria and helminthic co-infection during pregnancy causes fetomaternal haemorrhage and foetal growth retardation. This study determined the pooled burden of pregnancy malaria and helminthic co-infection in sub-Saharan Africa. CINAHL, EMBASE, Google Scholar, Scopus, PubMed, and Web of Science databases were used to retrieve data from the literature, without restricting language and publication year. The Joanna Briggs Institute's critical appraisal tool for prevalence studies was used for quality assessment. STATA Version 14.0 was used to conduct the meta-analysis. The I2 statistics and Egger's test were used to test heterogeneity and publication bias. The random-effects model was used to estimate the pooled prevalence at a 95% confidence interval (CI). The review protocol has been registered in PROSPERO, with the number CRD42019144812. In total, 24 studies (n = 14,087 participants) were identified in this study. The pooled analysis revealed that 20% of pregnant women were co-infected by malaria and helminths in sub-Saharan Africa. The pooled prevalence of malaria and helminths were 33% and 35%, respectively. The most prevalent helminths were Hookworm (48%), Ascaris lumbricoides (37%), and Trichuris trichiura (15%). Significantly higher malaria and helminthic co-infection during pregnancy were observed. Health systems in sub-Saharan Africa must implement home-grown innovative solutions to underpin context-specific policies for the early initiation of effective intermittent preventive therapy.

Erythrocyte miRNA regulators and malarial pathophysiology.

Pathophysiology of Plasmodium falciparum and Plasmodium vivax in malaria vis a vis host and the parasite genome interactions has been deciphered recently to present the biology of cerebral malaria, severe anaemia and placental malaria. Small non-coding RNAs have exhibited their potential to be considered as indicators and regulators of diseases. The malarial pathologies and their associated mechanisms mediated by miRNAs and their role in haematopoiesis and red cell-related disorders are elucidated. Evidence of miRNA carrying exosome-like vesicles released during infection, delivering signals to endothelial cells enhancing gene expression, resulting in parasite sequestration and complications leading to pathologies of cerebral malaria are important breakthroughs. Pregnancy malaria showed Plasmodium surface antigen promoted erythrocyte sequestration in the placental intervillous space, provoking disease development and assorted complications. Syncytiotrophoblast-derived microparticles during pregnancy and fetus development may predict pathophysiological progression on account of their altered miRNA cargoes in malaria.

Congenital toxoplasmosis and pregnancy malaria detection post-partum: Effective diagnosis and its implication for efficient management of congenital infection.

Congenital toxoplasmosis (CT) and pregnancy malaria (PM) have been individually reported to cause severe negative outcomes in pregnancies but the diagnostic method is still debatable. This study sought to estimate the prevalence of PM and CT single and co-infections in pregnant women by using various specimens including plasma and placental tissues. Genomic DNA extracted from the placenta, cord blood or blood of mothers was tested by PCR. Conventional method of immunodiagnosis was done for CT. We tested 79 pregnant women aged 18-42 years (mean: 28±1.06). Prevalence of Plasmodium falciparum infection determined by PCR on mother's peripheral blood specimen was 6.3% whiles 57.3% was recorded for placental tissues (p<0.01). PCR testing for placental tissues showed 29.2% positive for Toxoplasma gondii, whiles 76.0% of mothers had serum IgG against T. gondii. It should be noted that 6.3% of the placental tissues showed PCR positive for SAG 3, a marker of active infection in T. gondii. Although there were no enhanced foetal disorders at birth in our study, there is a possibility of active transmission of T. gondii from mothers to foetuses even in immune mothers. Our study suggests that foetuses were exposed to P. falciparum and T. gondii in utero, and placenta is a better specimen for PCR in detecting such episodes. In cases of PCR-positive samples, clinical follow-up after birth may be important.

Iron overload in Plasmodium berghei-infected placenta as a pathogenesis mechanism of fetal death.

Plasmodium infection during gestation may lead to severe clinical manifestations including abortion, stillbirth, intrauterine growth retardation, and low birth weight. Mechanisms underlying such poor pregnancy outcomes are still unclear. In the animal model of severe placental malaria (PM), in utero fetal death frequently occurs and mothers often succumb to infection before or immediately after delivery. Plasmodium berghei-infected erythrocytes (IEs) continuously accumulate in the placenta, where they are then phagocytosed by fetal-derived placental cells, namely trophoblasts. Inside the phagosomes, disruption of IEs leads to the release of non-hemoglobin bound heme, which is subsequently catabolized by heme oxygenase-1 into carbon monoxide, biliverdin, and labile iron. Fine-tuned regulatory mechanisms operate to maintain iron homeostasis, preventing the deleterious effect of iron-induced oxidative stress. Our preliminary results demonstrate that iron overload in trophoblasts of P. berghei-infected placenta is associated with fetal death. Placentas which supported normally developing embryos showed no iron accumulation within the trophoblasts. Placentas from dead fetuses showed massive iron accumulation, which was associated with parasitic burden. Here we present preliminary data suggesting that disruption of iron homeostasis in trophoblasts during the course of PM is a consequence of heme accumulation after intense IE engulfment. We propose that iron overload in placenta is a pathogenic component of PM, contributing to fetal death. The mechanism through which it operates still needs to be elucidated.

Pregnancy malaria: cryptic disease, apparent solution

Malaria during pregnancy can be severe in non-immune women, but in areas of stable transmission, where women are semi-immune and often asymptomatic during infection, malaria is an insidious cause of disease and death for mothers and their offspring. Sequelae, such as severe anaemia and hypertension in the mother and low birth weight and infant mortality in the offspring, are often not recognised as consequences of infection. Pregnancy malaria, caused by Plasmodium falciparum, is mediated by infected erythrocytes (IEs) that bind to chondroitin sulphate A and are sequestered in the placenta. These parasites have a unique adhesion phenotype and distinct antigenicity, which indicates that novel targets may be required for development of an effective vaccine. Women become resistant to malaria as they acquire antibodies against placental IE, which leads to higher haemoglobin levels and heavier babies. Proteins exported from the placental parasites have been identified, including both variant and conserved antigens, and some of these are in preclinical development for vaccines. A vaccine that prevents P. falciparum malaria in pregnant mothers is feasible and would potentially save hundreds of thousands of lives each year.