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Background Malaria in pregnancy (MiP) has been associated with fetal growth restriction, the underlying pathogenic mechanisms of which remain poorly understood. Malaria in pregnancy is suspected to induce abnormalities in placental vascularization, leading to impaired placental development. Our study evaluated MIP's effect on uterine artery (UtA) and umbilical artery (UA) blood flow. Methods The analysis included 253 Beninese women followed throughout pregnancy and screened monthly for submicroscopic and microscopic malaria. Uterine artery Doppler measurement was performed once between 21 and 25 weeks' gestation (wg), and UA Doppler measurement was performed 1–3 times from 28 wg. Linear and logistic regression models were used to assess the effect of malaria infections on UtA Doppler indicators (pulsatility index and presence of a notch), whereas a logistic mixed model was used to assess the association between malaria infections and abnormal UA Doppler (defined as Z-score ≥2 standard deviation or absent/reversed UA end-diastolic flow). Results Primigravidae represented 7.5% of the study population; 42.3% of women had at least 1 microscopic infection during pregnancy, and 29.6% had at least 1 submicroscopic infection (and no microscopic infection). Both microscopic and submicroscopic infections before Doppler measurement were associated with the presence of a notch (adjusted odds ratio [aOR] 4.5, 95% confidence interval [CI] = 1.2–16.3 and aOR 3.3, 95% CI =.9–11.9, respectively). No associations were found between malaria before the Doppler measurement and abnormal UA Doppler. Conclusions Malaria infections in the first half of pregnancy impair placental blood flow. This highlights the need to prevent malaria from the very beginning of pregnancy. [ABSTRACT FROM AUTHOR]

Background: Malaria in early pregnancy occurs at a time when the placenta is developing, with possible consequences for placental function and fetal growth. We assessed the association between first trimester malaria and fetal growth documented through repeated ultrasound scans.Methods: The RECIPAL preconceptional cohort included 411 Beninese pregnant women followed from 7 weeks' gestation (wg) until delivery. Among them, 218 had 4 scans for fetal monitoring at 16, 22, 28, and 34 wg. Multivariate seemingly unrelated regression models were used to assess association of microscopic malaria in the first trimester (<15 wg) with abdominal circumference, head circumference, biparietal diameter, and femur length throughout pregnancy.Results: Of 39% (86/218) of women with at least 1 microscopic malarial infection during pregnancy, 52.3% (45/86) were infected in the first trimester. Most women (88.5%) were multiparous. There was no association between adjusted z-scores for fetal growth parameters and first trimester malaria. Parity, newborn sex, socioeconomic level, and maternal body mass index significantly influenced fetal growth.Conclusions: In a context where malaria infections in pregnancy are well detected and treated, their adverse effect on fetal growth may be limited. Our results argue in favor of preventing and treating infections as early as the first trimester. [ABSTRACT FROM AUTHOR]

Background Harmful maternal and neonatal health outcomes result from malaria in pregnancy, the prevention of which primarily relies on intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP). The World Health Organization recommends IPTp-SP in sub-Saharan Africa, but implementation is highly heterogeneous and often suboptimal in terms of the number of doses and their timing. In this study, we assessed the impact of this heterogeneity on malaria in pregnancy, mainly with respect to submicroscopic Plasmodium falciparum infections. Methods We used data from 273 Beninese women followed throughout pregnancy. Screening for P. falciparum infections, using both microscopy-based and polymerase chain reaction (PCR)–based methods, was performed monthly, and information on IPTp-SP doses was collected. Gestational age was estimated by repeated ultrasound scans. Using a negative binomial model, we investigated the effect of IPTp-SP doses and timing after 17 weeks of gestation on the number of P. falciparum infections, focusing on submicroscopic infections detectable only by PCR. Results At least 2 IPTp-SP doses were taken by 77.3% of the women. The median gestational age at the first IPTp-SP dose was 22 weeks. A late first IPTp-SP dose (>21.2 weeks) was marginally associated with an increased number of P. falciparum infections (adjusted incidence rate ratio [aIRR] = 1.3; P  = .098). The number of IPTp-SP doses was not associated with the number of submicroscopic infections (aIRR = 1.2, P  = .543). Conclusions A late first IPTp-SP dose failed to provide optimal protection against P. falciparum , especially submicroscopic infections. This highlights the need for a new antimalarial drug for IPTp that could be taken early in pregnancy. [ABSTRACT FROM AUTHOR]

Background Malaria infections in the first trimester of pregnancy are frequent and deleterious for both mother and child health. To investigate if these early infections are newly acquired or already present in the host, we assessed whether parasites detected before pregnancy and those detected in early pregnancy are the same infection. Methods We used data from the preconceptional "RECIPAL" study (Benin, 2014–2017). Sixty-three pregnant women of 411 included who had a malaria infection detected by quantitative polymerase chain reaction both before pregnancy and at the first antenatal care (ANC) visit were selected for this study. Two highly polymorphic markers, msp-2 and glurp , and a fragment-analysis method were used to enumerate the Plasmodium falciparum genotypes and to quantify their proportions within isolates. An infection was considered as persistent when identical msp-2 and glurp genotypes were found in the corresponding prepregnancy and early-pregnancy samples. Results The median time between the 2 malaria screenings was 3 months. The median gestational age at the first ANC visit was 6.4 weeks. Most infections before pregnancy were submicroscopic infections. Based on both msp-2 and glurp genotyping, the infection was similar before and in early pregnancy in 46% (29/63) of cases. Conclusions Almost half of P. falciparum infections detected in the first trimester originate before pregnancy. Protecting young women from malaria infection before pregnancy might reduce the prevalence of malaria in early pregnancy and its related poor maternal and birth outcomes. [ABSTRACT FROM AUTHOR]

Background In the context of global malaria elimination efforts, special attention is being paid to submicroscopic Plasmodium falciparum infections. In pregnant, sub-Saharan African women, such infections are more prevalent than microscopic infections, and are thought to have adverse effects on both mothers' and newborns' health. However, no study has studied the dynamics and determinants of these infections throughout pregnancy. Retard de Croissance Intra-uterin et Paludisme (RECIPAL), a preconception cohort study carried out in Benin between 2014 and 2017, represented a unique opportunity to assess this issue. Methods We used data from 273 pregnant Beninese women who were followed-up from preconception to delivery. We studied the dynamics of and factors influencing submicroscopic (and microscopic) P. falciparum infections during the 3 trimesters of pregnancy, using an ordinal logistic mixed model. Results The incidence rate of submicroscopic P. falciparum infections during pregnancy was 12.7 per 100 person-months (95% confidence interval [CI] 10.8–14.9), compared to 6.7 per 100 person-months (95% CI 5.5–8.1) for microscopic infections. The prevalences were highest in the first trimester for both submicroscopic and microscopic infections. After adjustment for potential confounding factors, we found that those of young age and those with a submicroscopic P. falciparum infection prior to pregnancy were at significantly higher risks of submicroscopic and microscopic infections throughout pregnancy, with a more pronounced effect in the first trimester of pregnancy. Conclusions The first trimester of pregnancy is a particularly high-risk period for P. falciparum infection during pregnancy, especially for the youngest women. Malaria prevention tools covering the preconception period and early pregnancy are urgently needed to better protect pregnant women and their newborns. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum-infected erythrocytes bind to specific endothelial cell receptors via members of the PfEMP1 family exported onto the erythrocyte surface. These interactions are mediated by different types of cysteine-rich interdomain region (CIDR) domains found in the N-terminal region of all PfEMP1. CIDRα1 domains bind endothelial protein C receptor (EPCR), CIDRα2-6 domains bind CD36, whereas the receptor specificity of CIDRβ/γ/δ domains is unknown.Methods: In this study, we investigated the level of immunoglobulin (Ig)G targeting the different types of PfEMP1 CIDR during the first year of life. We used plasma collected longitudinally from children of pregnant women who had been followed closely through pregnancy.Results: Antibodies to CIDRα1 domains were more frequent in cord blood compared with antibodies to CIDRα2-6 domains. Higher IgG levels to EPCR-binding CIDRα1 variants positively correlated with the timing of first infections. Antibodies to all PfEMP1 types declined at similar rates to the point of disappearance over the first 6 months of life. At 12 months, children had acquired antibody to all types of CIDR domains, mostly in children with documented P falciparum infections.Conclusions: These observations agree with the notion that the timing and phenotype of first P falciparum infections in life are influenced by the immune status of the mother. [ABSTRACT FROM AUTHOR]

Background In sub-Saharan Africa, malaria in the first half of pregnancy is harmful for both the mother and her fetus. However, malaria in the first trimester of pregnancy, when women are usually not protected against malaria, has been little investigated. For the first time, we assessed the effects of malaria in the first trimester on maternal and birth outcomes using a preconceptional study design. Methods From June 2014 to March 2017, 1214 women of reproductive age were recruited and followed monthly until 411 became pregnant. The pregnant women were then followed from 5–6 weeks of gestation until delivery. Path analysis was used to assess the direct effect (ie, not mediated by malaria in the second or third trimester) of malaria in the first trimester on maternal anemia and poor birth outcomes. The cumulative effect of infections during pregnancy on the same outcomes was also evaluated. Results The prevalence of malaria infections in the first trimester was 21.8%. Malaria in the first trimester was significantly associated with maternal anemia in the third trimester (adjusted odds ratio 2.25, 95% confidence interval 1.11–4.55). While we did not find evidence of any direct effect of first trimester malaria infections on birth outcomes, their association with infections later in pregnancy tended to increase the risk of low birth weights. Conclusions Malaria infections in the first trimester were highly prevalent and have deleterious effects on maternal anemia. They highlight the need for additional preventive measures, starting in early pregnancy or even before conception. [ABSTRACT FROM AUTHOR]

Background: There is a lack of data on the burden of malaria in the first trimester of pregnancy in Africa, mainly because pregnant women generally attend the maternity clinic late. Bed nets are rarely provided to women before the second trimester of pregnancy and intermittent preventive treatment with sulfadoxine-pyrimethamine is not recommended before the second trimester, leaving women insufficiently or not protected in early pregnancy.Methods: To assess the burden of first trimester malaria, 387 women were followed up monthly from preconception to delivery. They were screened for malaria monthly from early pregnancy until delivery. A logistic multilevel model was used to assess maternal factors associated with malaria during the first trimester.Results: The proportion of women with at least 1 microscopic malaria infection during the first trimester of pregnancy was 20.8%. Women infected with malaria preconception were more likely to be infected during the first trimester (adjusted odds ratio: 2.68; 95% confidence interval, 1.24-5.78). Early gestational age was also positively correlated with malaria infection.Conclusions: Using a preconceptional study design, we showed that malaria was highly prevalent in early pregnancy. This calls for the assessment of new strategies that could protect women as soon as the first trimester. [ABSTRACT FROM AUTHOR]

Background: Few studies have evaluated the effect of malaria on intrauterine growth restriction on the basis of the fetal growth rate, rather than just the small-for-gestational age z score. Here, we assessed the impact of malaria on IUGR, using data from a longitudinal, ultrasonography-based follow-up study of Beninese women.Methods: A total of 1016 women were followed up from gestational week 17 to delivery. Malaria was detected every month. Women underwent ultrasonography 4 times for gestational age determination and fetal biometry. We assessed the effect of malaria on birth weight-for-gestational age z score (n = 735 women) and fetal growth velocity (n = 664), defined as a change in fetal weight z score over time.Results: Malaria was detected in 43% of women. Fetal growth velocity was negative overall, decreasing further at the end of the third trimester. Women with ≥2 malarial parasite infections tended to have lower z scores than uninfected women. Malaria both in early and late pregnancy was associated with a reduction in fetal growth velocity, which occurred either immediately or with a delay after infection.Discussions: We confirmed the deleterious effect of malaria during both early and late pregnancy on fetal growth. This stresses the importance of starting preventive measures against malaria as early as possible during pregnancy. [ABSTRACT FROM AUTHOR]

Background. Molecular, as opposed to microscopic, detection measures the real prevalence of Plasmodium falciparum infections. Such occult infections are common during pregnancy but their impact on pregnancy outcomes is unclear. We performed a longitudinal study to describe that impact. Methods. In a cohort of 1037 Beninese pregnant women, we used ultrasound to accurately estimate gestational ages. Infection with P. falciparum, hemoglobin concentration, use of intermittent preventive treatment during pregnancy (IPTp) for malaria, and other parameters were recorded during pregnancy. Using multivariate analyses, we evaluated the impact of submicroscopic infections on maternal anemia, premature birth, and low birth weight. Results. At inclusion, polymerase chain reaction (PCR) and microscopy detected infection in 40% and 16% of women, respectively. The proportion infected declined markedly after 2 doses of IPTp but rebounded to 34% (by PCR) at delivery. Submicroscopic infections during pregnancy were associated with lower mean hemoglobin irrespective of gravidity, and with increased anemia risk in primigravidae (odds ratio [OR], 2.23; 95% confidence interval [CI], .98-5.07). Prospectively, submicroscopic infections at inclusion were associated with significantly increased risks of low birth weight in primigravidae (OR, 6.09; 95% CI, 1.16-31.95) and premature births in multigravidae (OR, 2.25; 95% CI, 1.13-4.46). Conclusions. In this detailed longitudinal study, we document the deleterious impact of submicroscopic P. falciparum parasitemia during pregnancy on multiple pregnancy outcomes. Parasitemia occurs frequently during pregnancy, but routine microscopic and rapid diagnostic tests fail to detect the vast majority of episodes. Our findings imply caution in any revision of the current strategies for prevention of pregnancy-associated malaria. [ABSTRACT FROM AUTHOR]

Background. Plasmodium falciparum is responsible for severe malaria, including pregnancy-associated malaria (PAM). During intra-erythrocytic maturation, the infected erythrocyte (iE) membrane is modified by insertion of parasite-derived proteins, primarily consisting of variant surface antigens such as P. falciparum erythrocyte membrane protein-1. Methods. To identify new PAM-specific parasite membrane proteins, we conducted a mass spectrometry-based proteomic study and compared the protein expression profiles of 10 PAM and 10 uncomplicated malaria (UM) samples. Results. We focused on the 454/1139 membrane-associated and hypothetical proteins for comparative analysis. Using filter-based feature-selection methods combined with supervised data analysis, we identified a subset of 53 proteins that distinguished PAM and UM samples. Up to 19/20 samples were correctly assigned to their respective clinical group. A hierarchical clustering analysis of these 53 proteins based on the similarity of their expression profiles revealed 2 main clusters of 40 and 13 proteins that were under- or over-expressed, respectively, in PAM. Conclusions. VAR2CSA is identified and associated with PAM, validating our experimental approach. Other PAM-predictive proteins included PFI1785w, PF14_0018, PFB0115w, PFF0325c, and PFA_0410w. These proteomics data demonstrate the involvement of selected proteins in the pathophysiology of PAM, providing new insights for the definition of potential new targets for a vaccine against PAM. [ABSTRACT FROM AUTHOR]

Background. Plasmodium falciparum-infected erythrocytes (IEs) adhere to host cell receptors, allowing parasites to sequester into deep vascular beds of various organs. This defining phenomenon of malaria pathogenesis is key to the severe clinical complications associated with cerebral and placental malaria. The principal ligand associated with the binding to chondroitin sulfate A (CSA) that allows placental sequestration of IEs is a P. falciparum erythrocyte membrane protein 1 (PfEMP1) family member encoded by the var2csa gene. Methods. Here, we investigated the transcription pattern of var genes by real-time polymerase chain reaction, the expression of VAR2CSA, protein by flow cytometry, and the CSA-binding ability of IEs collected at different stages of pregnancy using a static-based Petri dish assay. Results. Through comparison with the profiles of isolates from nonpregnant hosts, we report several lines of evidence showing that parasites infecting women during pregnancy preferentially express VAR2CSA protein, and that selection for the capacity to adhere to CSA via VAR2CSA expression occurs early in pregnancy. Conclusions. Our data suggest that the placental tropism of P. falciparum is already established in the first trimester of pregnancy, with consequent implications for the development of the pathology associated with placental malaria. [ABSTRACT FROM AUTHOR]

In tropical countries, malaria and hypertension are common diseases of pregnancy. They have physiopathologic similarities such as placental ischemia, endothelial dysfunction, and production of proinflammatory cytokines. Recent findings suggested their possible link. The authors conducted a case-control study to explore the relation between malaria and hypertension at Guediawaye, a hypoendemic malarial setting in Senegal. Cases were pregnant women admitted to the delivery unit for hypertension. Controls were pregnant women admitted for normal delivery, without any history of hypertension or proteinuria during the present pregnancy. Malarial infection was determined by placental tissue examination. From January to December 2002, 77 cases of gestational hypertension, 113 cases of preeclampsia, 59 cases of eclampsia, and 241 controls were enrolled. Placental malarial infection (PMI) was present in 14 cases (6.3%) and in 15 controls (6.2%). The prevalence of PMI was 4.6% for eclampsia, 4.0% for preeclampsia, and 11.6% for gestational hypertension. In multivariate analysis, PMI appeared to be an independent risk factor for gestational hypertension (adjusted odds ratio = 2.7, 95% confidence interval: 1.0, 7.6). The authors found an association between PMI and nonproteinuric hypertension in women living in a malaria-hypoendemic area. The exact significance of such relation should be clarified in further studies in different settings of malarial endemicity. [ABSTRACT FROM PUBLISHER]

Background. In the context of the increasing resistance to sulfadoxine-pyrimethamine (SP), we evaluated the efficacy of mefloquine (MQ) for intermittent preventive treatment during pregnancy (IPTp). Methods. A multicenter, open-label equivalence trial was conducted in Benin from July 2005 through April 2008.Women of all gravidities were randomized to receive SP (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or 15 mg/kg MQ in a single intake twice during pregnancy. The primary end point was the proportion of low- birth-weight (LBW) infants (body weight, <2500 g; equivalence margin, 5%). Results. A total of 1601 women were randomized to receive MQ (n = 802) or SP (n = 799). In the modified intention-to-treat analysis, which assessed only live singleton births, 59 (8%) of 735 women who were given MQ and 72 (9.8%) of 730 women who were given SP gave birth to LBW infants (difference between low birth weights in treatment groups, -1.8%; 95% confidence interval [CI], -4.8% to 1.1%]), establishing equivalence between the drugs. The per-protocol analysis showed consistent results. MQ was more efficacious than SP in preventing placental malaria (prevalence, 1.7% vs 4.4% of women; P = .005), clinical malaria (incidence rate, 26 cases/10,000 person-months vs. 68 cases/10,000 person-months; P = .007), and maternal anemia at delivery (as defined by a hemoglobin level <10 g/dL) (prevalence, 16% vs 20%; marginally significant at P = .09). Adverse events (mainly vomiting, dizziness, tiredness, and nausea) were more commonly associated with the use of MQ (prevalence, 78% vs 32%; P < 10-3). One woman in the MQ group had severe neuropsychiatric symptoms. Conclusions. MQ proved to be highly efficacious-both clinically and parasitologically-for use as IPTp. However, its low tolerability might impair its effectiveness and requires further investigations. Clinical Trials Registration. NCT00274235. [ABSTRACT FROM AUTHOR]

Background. Pregnancy-associated malaria (PAM) is precipitated by the accumulation of parasites in the placental intervillous spaces and causes maternal anemia and low birth weight. In PAM, placental parasites adhere to chondroitin sulfate A (CSA) through a unique set of variant surface antigens (VSAPAM). Several studies have shown that 1 var gene, var2csa, is transcribed at high levels and expressed in CSA-binding Plasmodium falciparum parasites. Methods. Plasma levels of anti-VAR2CSA immunoglobulin G (IgG) in Senegalese women were measured during pregnancy by enzyme-linked immunosorbent assay, using 3 recombinant proteins representing 3 domains of the var2csa gene product. Results. The 3 recombinant proteins were specifically recognized by plasma from pregnant women but not by control plasma. A parity-dependent recognition pattern was observed with 2 of the 3 VAR2CSA antigens. A kinetic study demonstrated that a single P. falciparum infection was able to trigger a VAR2CSA-specific antibody response. Among women with infected placentas, women with high anti-VAR2CSA IgG levels at enrollment were more likely to present with a past infection than with an acute/chronic infection. Conclusions. Anti-VAR2CSA IgGs are involved in clinical protection against pregnancy-associated malaria and strengthens the hope for making a VAR2CSA-based vaccine. [ABSTRACT FROM AUTHOR]

A recombinant Duffy binding-like (DBL)- gamma domain from a previously identified placental isolate, 732, was expressed by use of the baculovirus/insect cell system and was purified in milligram quantities. The recombinant protein binds specifically to chondroitin sulfate A (CSA) and inhibits CSA binding by placental infected erythrocytes (IEs). Polyclonal antibodies raised against the domain recognized the surfaces of live IEs from CSA-adherent clinical placental isolates. These antibodies also abrogated the in vitro binding of IEs to CSA. The 732 DBL-3 gamma domain was specifically recognized by plasma from pregnant women but not by plasma from control subjects. In addition, the protein was, comparatively, significantly more reactive with plasma from women with infected placentas, strongly suggesting that the 732 DBL-3 gamma domain carries preferentially IE-expressed immunogenic epitopes. High levels of plasma antibodies to the recombinant domain were associated with reduced placental parasite density. This is the first report of a recombinant DBL- gamma domain derived from a placental isolate that shows CSA-binding properties. Copyright © 2005 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

A recombinant Duffy binding-like (DBL)-γ domain from a previously identified placental isolate, 732, was expressed by use of the baculovirus/insect cell system and was purified in milligram quantities. The recombinant protein binds specifically to chondroitin sulfate A (CSA) and inhibits CSA binding by placental infected erythrocytes (IEs). Polyclonal antibodies raised against the domain recognized the surfaces of live IEs from CSA-adherent clinical placental isolates. These antibodies also abrogated the in vitro binding of IEs to CSA. The 732 DBL-3γ domain was specifically recognized by plasma from pregnant women but not by plasma from control subjects. In addition, the protein was, comparatively, significantly more reactive with plasma from women with infected placentas, strongly suggesting that the 732 DBL-3γ domain carries preferentially IEexpressed immunogenic epitopes. High levels of plasma antibodies to the recombinant domain were associated with reduced placental parasite density. This is the first report of a recombinant DBL-g domain derived from a placental isolate that shows CSA-binding properties. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum parasites that bind to chondroitin sulphate A (CSA) express unique variant surface antigens that are involved in the placental sequestration that precipitates pregnancy-associated malaria (PAM). Two var gene subfamilies, van csa and var2csa, have been associated with CSA binding. We show here that placental P. falciparum isolates highly transcribed var2csa but not var1csa. var2csa was not transcribed or was only minimally transcribed by parasites isolated from nonpregnant women. Placental parasites that effectively bound to placental chondroitin sulphate proteoglycans transcribed higher levels of van2csa. In pregnant women, levels of van2csa transcription and plasma anti- VAR2CSA immunoglobulin G were associated. These findings support the idea that VAR2CSA plays a crucial role in PAM and strengthen the rationale for the development of VAR2CSA-based vaccines. [ABSTRACT FROM AUTHOR]

Objectives: The risk of malaria infection is increased during pregnancy, and many countries recommend chloroquine prophylaxis in pregnant women, despite Plasmodium falciparum chloroquine resistance. Chloroquine resistance is associated with the pfcrt gene K76T mutation. The aim of this study was to compare the prevalence rate of pfcrt T76 mutation in P. falciparum isolates from infected pregnant and non-pregnant individuals from Senegal.Methods: The study was conducted in the rural maternity hospital of Thiadiaye, Senegal, where malaria is seasonal. Sixty-nine P. falciparum isolates from infected women were collected at delivery. These women were part of a cohort study; they were followed from their first antenatal visit and advised to take chloroquine prophylaxis. For each woman, the earliest P. falciparum-infected blood sample was also used. A control group of 49 non-pregnant individuals with asymptomatic P. falciparum infection was enrolled.Results: During pregnancy, prevalence of T76 mutant parasites was higher than in the 49 non-pregnant controls (P?<0.001). Among pregnant women, this rate was highest at delivery (P=0.06), and tended to be higher in women who had taken chloroquine prophylaxis, as assessed in urine samples (P=0.08).Conclusions: Chloroquine prophylaxis is responsible for increased drug consumption and increased drug pressure that may lead to the selection of drug-resistant parasites. This is the first report showing that P. falciparum-infected pregnant women harbour pfcrt T76 mutant parasites more often than non-pregnant individuals, and that the prevalence of this mutation is higher at term than earlier during pregnancy. [ABSTRACT FROM AUTHOR]

Background. Pregnancy-associated malaria is characterized by selection and multiplication, in the placenta, of a distinct population of Plasmodium falciparum expressing particular variant surface antigens (VSAs) that adhere to chondroitin sulfate A (GSA). Methods. The adhesion of 40 freshly collected placental parasite isolates to bovine GSA and human placental low-sulfated chondroitin proteoglycans (GSPGs) was investigated. Plasma samples from 30 pregnant women were used to test, by flow cytometry, their recognition of and their adhesion-inhibition capacity toward 6 of these isolates. Results. Adhesion to GSA and GSPGs varied between isolates but was strongly correlated between receptors (P < .001). Adhesion of isolates to receptors strongly and negatively correlated with low birth weight (LBW) of the neonate (odds ratio [95% confidence interval], 5.2 [1.1-25.1]). In plasma samples from pregnant women, the level of specific immunoglobulin G against each placental isolate (anti-VSAPAP) strongly correlated with the level of anti-VSAPAP antibodies against all other isolates (P < .05) and increased with parity in all isolates (P < .01). Conversely, adhesion-inhibitory antibodies did not correlate with isolates or with the level of anti-VSAPAP antibodies. Conclusion. The level of adhesion of placental parasites to chondroitin sulfate receptors is an important risk factor for LBW. Parasite heterogeneity suggests that they are composed of mixed adhesion phenotypes capable of inducing immune responses to a range of different and overlapping targets. [ABSTRACT FROM AUTHOR]

Background. During healthy pregnancy, T helper (Th) 1-type and inflammatory-type responses are down-regulated, and Th2-type and proinflammatory-type responses predominate. in Plasmodium falciparum-infected females, these responses induce enhanced production of tumor necrosis factor-α and interferon-β. Methods. To assess the respective implication of monocytes and T cells in this placental immunomodulation, we cocultured cells from delivering females living in an area where malaria is endemic. Monocytes and T cells from both peripheral and intervillous blood were crossed in in vitro cultures, to compare the proliferative response to several antigens. Moreover, monocyte cell-surface molecules were quantified by flow cytometry. Results. Coculture results confirmed placental immunomodulation and suggested that the most affected cells are not the intervillous monocytes, which are as able to present the antigen as the peripheral monocytes, but the intervillous T cells. Monocyte staining showed significant increases in human leukocyte antigen D-related, CD54, CD80, and CD86 surface markers in intervillous blood, compared with peripheral blood, which suggests a relative activation of monocytes in the placenta. Conclusion. A state of T cell deactivation and monocyte activation is present at delivery. The T cell deactivation in reaction to purified protein derivative could be explained by the presence of local T cell immunoregulatory factors. [ABSTRACT FROM AUTHOR]

The consequences of pregnancy-associated malaria on a child’s health have been poorly investigated. Malarial infection of the placenta seems to result in a higher susceptibility of children to the parasite during their first year of life. In 1993–1995, the authors investigated the role of antibodies in variable surface antigens (VSA) specific to chondroitin sulfate A (CSA)-binding parasites to assess the parasitologic status of the child. Flow cytometry was used to measure levels of antibodies to VSA from CSA-selected and -unselected parasite lines in the cord blood of 79 newborns in Ebolowa, Cameroon. These newborns were subsequently followed up for 2 years to determine the date of first occurrence of blood parasites and mean parasite density during follow-up. Maternally transmitted antibodies to VSA expressed by CSA-binding parasites, but not antibodies to any other specificity, were negatively related to time of first appearance of Plasmodium falciparum in a child’s blood and were positively related to mean parasite density during the first 2 years of life. If maternal infection is thought to be the main mechanism influencing susceptibility of the newborn to malaria, antibodies to VSA may better denote maternal malaria infection during almost the entire pregnancy as opposed to placental blood smear reflecting infection during the last few months of pregnancy. [ABSTRACT FROM PUBLISHER]

Otherwise clinically immune women in areas endemic for malaria are highly susceptible to Plasmodium falciparum malaria during their first pregnancy. Pregnancy-associated malaria (PAM) is characterized by placental accumulation of infected erythrocytes that adhere to chondroitin sulfate A (CSA). Susceptibility to PAM decreases with increasing parity, apparently due to acquisition of antibodies directed against the variant surface antigens (VSAs) that mediate the adhesion to CSA (VSA[sub CSA]). This study found that levels of VSA[sub CSA]-specific antibodies depend on endemicity, that anti-VSA[sub CSA] IgG is acquired during gestation week 20, and that plasma levels of the antibodies decline during the postpartum period. There is evidence that VSA[sub CSA]-specific antibodies are linked to placental infection and that high antibody levels contribute to the control of placental infection by inhibiting parasite adhesion to CSA. Data suggest that VSA[sub CSA] is a target for vaccination against PAM. [ABSTRACT FROM AUTHOR]

In utero transmission of HIV-1 has been demonstrated and may account for around 10–20% of all materno–fetal HIV-1 transmission. The possible routes for such transmission are transannexial or transplacental. In both cases, the microenvironment (cytokines and chemokines) at the placental interface could be an important regulatory factor in viral transmission. We therefore performed explant cultures of placental villi, and isolated purified trophoblasts, from term placentae obtained from HIV-1-seropositive and HIV-1-seronegative women in order to assess and compare the cytokine and chemokine secretion profiles using ELISA and semiquantitative RT-PCR. No major differences could be seen in the secretions of cytokines and chemokines at the level of whole placental tissue in HIV-1-positive and HIV-1-negative women. However, variations were observed in the expression of inflammatory cytokines and chemokines from trophoblastic cells, depending on the status of HIV-1 infection of the mothers but not the babies, all of which remained uninfected. The significance of these data is discussed. [ABSTRACT FROM AUTHOR]

Presents information on a study which measured cytokines secreted in cultures of chorionic villi, placental blood cells and serum in term placentas from 88 malaria-infected and non-infected Cameroon women. Materials and methods; Analysis of placentas; In vitro cytokine production by cultures.

Background: Individuals may be homozygous (SS) or heterozygous (AS) sickle cell gene carriers or have normal adult haemoglobin (AA). Haemoglobin S could have a protective role against malaria but evidence is sparse and the operating mechanisms are poorly known.Methods: We followed two cohorts of children. The first was enrolled at birth (156 newborn babies) and the second at 24-36 months old (84 children). Both cohorts were followed for 30 months; monthly for parasitological data and half yearly for immunological data.Results: In the first cohort, 22%, and in the second 13% of children were AS. Whatever their age parasite prevalence rates were similar in AA and AS individuals. Mean parasite densities increased less rapidly with age in AS than in AA children, and were significantly lower in AS than in AA children >48 months old. The AA children tended to be more often admitted to hospital than AS children (22% versus 11%, NS). Both anti-Plasmodium falciparum and anti-Pfl55/RESA antibody rates increased more rapidly in AA than in AS children. Conversely, the prevalence rate of cellular responders to the Pfl55/RESA antigen was similar in AA and AS children during the first 2 years of life, then it was higher in AS than in AA children.Conclusions: Sickle cell trait related antimalarial protection varies with age. The role of the modifications of the specific immune response to P. falciparum in explaining the protection of AS children against malaria is discussed. [ABSTRACT FROM AUTHOR]

Mechanisms responsible for the increase in malaria susceptibility during pregnancy, and in particular during the first pregnancy, have not been elucidated. T and B cell responses to leucoagglutinin, bacille Calmette-Guérin (BCG) and to six Plasmodium falciparum antigens were longitudinally investigated in 33 pregnant women during their first pregnancy, after delivery, and during second pregnancy. Parasitological data obtained from the same women during and after the first pregnancy demonstrated the higher risk of P. falciparum infection during this pregnancy. Plasma levels of antibodies to Pf155/RESA were lower during pregnancy than after delivery. Conversely, antibodies to P. falciparum asexual blood stages were higher during pregnancy than after delivery, suggesting that during pregnancy the regulation of antibody production may be variously impaired depending upon the antigens. The most striking finding of the present study is the impairment of the IL-2 cellular response during the first pregnancy. Conversely, proliferative responses, as well as IL-4 and interferon-gamma (IFN-γ) responses, were either unaffected or moderately enhanced. No difference in humoral and cellular responses was observed between first and second pregnancy. The impairment of the IL-2 responses involved the response to malaria peptides and proteins, as well as the response to non-malarial antigens and to the mitogen leucoagglutinin. Thus, the alteration of malaria immunity might rather fall into the general frame of the depression of cellular immunity during pregnancy than involve a specific malaria phenomenon. [ABSTRACT FROM AUTHOR]

We have adapted the enzyme-linked immunospot assay (ELISPOT) to enumerate the cells from Plasmodium falciparum-primed donors that produce IgG in vitro in response to malaria antigens. In vitro activation of cell cultures with two synthetic peptides (EENVEHDA)4, and (LGRSGGDIIKMQTL) corresponding to immunodominant T cell epitopes of the ring-infected erythrocyte surface antigen (Pf 155/RESA) gave specific antibody-secreting cells (ASC) in five and six of the 15 P. falciparum-primed donors from Cameroon, Antibodies produced after a stimulation by synthetic peptides reacted also with total parasite proteins. However, crude P. falciparum antigen did not trigger a higher number of cells than did synthetic peptides. The absence of significant relation between the presence of sera antibodies and in vitro ASC against the same peptide suggests that the kinetics of circulating primed lymphocytes and antibodies are different. We evaluated 0.04-0.29% of peripheral blood B cells to be the frequency of memory cells specific to a single Pf155/RESA epitope in these donors. This study suggests that the ELISPOT assay should permit the analysis of B cell responses to malarial antigens at the single-cell level and its applicability to epidemiological field studies. This assay should be well suited to the identification of T helper epitopes capable of inducing the production of antibodies by human B cells, and will constitute an important tool for the selection of immunogens to be included in a subunit vaccine. [ABSTRACT FROM AUTHOR]

In areas endemic for malaria, pregnant women frequently present with a placenta that has been parasitized by Plasmodium falciparum, an infection associated with a reduction in the birth weight of the offspring. However, the impact of placental infection on malaria-related morbidity during the infant's first years of life has not been investigated. Between 1993 and 1995, 197 children in southern Cameroon were followed weekly clinically and monthly parasltologically. The dates of first positive blood smear and the evolution of the parasite prevalence rates were compared between infants bom to mothers presenting with (n = 42) and without (n = 155) P. falciparum infection of the placenta. Infants born to placenta-infected mothers were more likely to develop a malaria infection between 4 and 6 months of age; then the difference progressively disappeared. Similarly, parasite prevalence rates were higher in placenta-infected infants from 5 to 8 months of age. Thus, malarial infection of the placenta seems to result in a higher susceptibility of infants to the parasite. This was not related to maternally transmitted antibodies, as specific antibody levels were similar in both groups of infants. A better understanding of the involved mechanisms may have important implications for the development of malaria control strategies. [ABSTRACT FROM AUTHOR]

In malaria-endemic areas, infants are relatively protected against malaria injection. Such protection is though to be related principally to the transplacental transfer of maternal antibodies. We measured total and Plasmodium falciparum-specific: IgG (including subclasses), IgM, and IgE antibodies in 154 paired maternal-cord serum samples from an area of meso- to hyperendemic malaria in South Cameroon. Among peripheral mother blood samples, total IgG and IgM were detected in all samples, IgE in all but two. Plasmodium falciparum-specific IgG were detected in all serum samples, IgM and IgE in >75% of samples. The prevalence rates of anti-P. falciparum IgG subclasses varied from 75% to 97%. With the exception of P. falciparum-specific IgG. all antibody class and subclass levels were lower in cord blood than in peripheral mother blood. Plasmodium falciparum-specific IgGl and IgG3 isotypes were transferred to the offspring more often and more efficiently than IgG2 and IgG4. The detection of total and P. falciparum-specific IgM and IgE in some cord some samples demonstrated that fetuses can mount humoral response against malaria parasites. We also determined whether transplacentally acquired antibodies protect against malaria infection by relating the antibody levels at birth to the risk of acquiring P. falciparum infection during the first 6 months of life. Among various classes and subclasses of P. falciparum-specific antibodies, only IgG2 were related to a decrease in the risk of acquiring a P. falciparum peripheral blood infection from birth to 6 months of age. [ABSTRACT FROM AUTHOR]

The adrenergic system and its relation with the renin-angiotensin-aldosterone system was studied in three groups of women with pregnancies of 20–38 weeks: group I of 16 normotensive controls, group II of 17 women with rest-responding hypertension (RRH) and group III of 18 women with permanent hypertension induced by pregnancy (PIH) (supine blood pressure > 140–90 mm Hg after eight days of home bed rest, disappearing after delivery). Blood samples were taken from fasting ambulatory women on a normal salt diet.Plasma epinephrine (PE) and plasma norepinephrine (PNE) (mean±s.e.m) were significantly higher in the PIH group than in the control and RRH groups: 135±28 v. 56±13 and 63± 17 pg/ml for PE and 387±91 v. 206 ± 32 and 200 ± 47 pg/ml for PNE.Plasma renin activity (PRA) was significantly higher in the RRH group than in the control and PIH groups (15–8 ± 2.3 v. 6.7±0.5 and 8.9±0.9 ng/ml/h). Plasma aldosterone (PA) was higher but not significantly in the RRH group (736 ± 122 v. 533 ± 52 and 502± 103 pg/ml).These data suggest that PIH is linked with activation of the adrenergic system whereas RRH is linked with activation of the RAA system. [ABSTRACT FROM PUBLISHER]

Most terrestrial prey species are assumed to assess predation risk by detecting predators directly rather than using cues of previous attacks on conspecifics. However, such cues might represent valuable information, and prey can be expected to respond to the presence of congeners killed by enemies. Such cues are available in aphid colonies attacked by parasitic wasps because they do not remove parasitized hosts from the colony. Colonies are thus often a mixture of healthy, parasitized, and killed aphids, which corpses (“mummies”) stay attached to the plant and can be encountered by live aphids. Aphids exhibit a dispersal polyphenism. Recent studies show that they produce more winged offspring when directly exposed to natural enemies or to alarm pheromone emitted by conspecifics. We hypothesized that aphids perceive the corpses of congeners killed by parasitoids and respond by increasing the production of winged morphs, but we surprisingly found the opposite. We determined the adaptive value of this response by analyzing the foraging behavior of parasitoids in aphid colonies with killed aphids (“mummies”). Parasitoid females responded to the presence of mummies by reducing both their time allocation and parasitism activity in the patch. The strategy of aphids to reduce emigration (i.e., they produce more wingless morphs when mummies are present) is adaptive because the presence of killed congeners reduces parasitoid pressure on colonies. This demonstrates that the remains of individuals killed by natural enemies can still have an ecological relevance in prey populations and that enemy-induced phenotypic plasticity depends on the type of predation cues. [ABSTRACT FROM AUTHOR]