Risk Factors for Placental Malaria, Sulfadoxine-pyrimethamine Doses, and Birth Outcomes in a Rural to Urban Prospective Cohort Study on the Bandiagara Escarpment and Bamako, Mali

BackgroundMalaria in Mali remains a primary cause of morbidity and mortality, with women at high risk during pregnancy for placental malaria (PM). We evaluated risk for PM and its association with birth outcomes in a rural to urban longitudinal cohort on the Bandiagara Escarpment and the District of Bamako. MethodsWe collected placental samples (N = 317) from 249 mothers who were participants in our longitudinal cohort study. A placental pathologist and research assistant evaluated the samples by histology in blinded fashion to assess PM infection stage and parasite density. We used generalized estimating equations (GEE) to model the odds of PM infection.ResultsPregnancies in Bamako, beyond secondary education, births in the rainy season (instead of the hot dry season), births in later years of the study, and births to women who had > 3 doses of sulfadoxine-pyrimethamine (SP) instead of no doses of SP were associated with reduced odds of experiencing PM (active and past infections combined). We found improved birth outcomes (+ 285 g birth weight, + 2 cm birth length, + 75 g placental weight) for women who had > 3 doses of SP compared to no doses, but did not detect a difference in birth weight or length for women who had 2 instead of > 3 SP doses. However, at 2 instead of > 3 doses placentas were 36 g lighter and the odds of low birth weight (< 2500 g) were 14% higher. Severe parasite densities were significantly associated with decreases in birth weight, birth length, and placental weight, as were chronic PM infections. The women who received no SP during pregnancy (7% of the study total) were younger and lacked primary school education. The women who received ≥ 3 doses of SP came from more affluent families.ConclusionsWomen who received no doses of SP during pregnancy experienced the most disadvantageous birth outcomes in both Bamako and on the Bandiagara Escarpment. Such women tended to be younger and to have had no primary school education. Targeting such women for antenatal care, which is the setting at which SP is most commonly administered in Mali, will have a more positive impact on public health than focusing on the increment from two to three doses of SP.

Assessing the Relationship Between Gravidity and Placental Malaria Among Pregnant Women in a High Transmission Area in Ghana

Background Malaria infection during pregnancy can cause significant morbidity and mortality to a pregnant woman, her foetus and newborn. In areas of high endemic transmission, gravidity is an important risk factor for infection, but there is a complex relationship with other exposure-related factors, and use of protective measures. This study investigated the association between gravidity and placental malaria (PM), among pregnant women aged 14-49 in Kintampo, a high transmission area of Ghana. Methods Between 2008-2011, as part of a study investigating the association between PM and malaria in infancy, pregnant women attending antenatal care (ANC) clinics in the study area were enrolled and followed up until delivery. The outcome of PM was assessed at delivery by placental histopathology. Multivariable logistic regression analyses were used to investigate the association between gravidity and PM, identify other key risk factors, and control for potential confounders. Pre-specified effect modifiers including area of residence, socio-economic score (SES), ITN use and IPTp-SP use were explored. Results The prevalence of PM was 65.9% in primigravidae, and 26.5% in multigravidae. After adjusting for age, SES and relationship status, primigravidae were shown to have over three times the odds of PM compared to multigravidae, defined as women with 2 or more previous pregnancies (adjusted OR=3.36 (95% CI 2.39-4.71), N=1808, P<0.001). The association appeared stronger in rural areas (OR for PG vs. MG was 3.79 (95% CI: 3.61-5.51) in rural areas; 2.09 (95% CI: 1.17- 3.71) in urban areas; P for interaction =0.07), and among women with lower socio-economic scores (OR for PG vs. MG was 4.73 (95% CI 3.08-7.25) amongst women with lower SES; OR=2.14 (95% CI 1.38-3.35) among women with higher SES; P for interaction =0.008. There was also evidence of lower risk among primigravidae with better use of the current preventive measures IPTp and LLIN. Conclusions The burden of PM is most heavily focused on primigravidae of low SES living in rural areas of high transmission. Programmes should prioritize primigravidae and young women of child-bearing age for interventions such as LLIN distribution, educational initiatives and treatment to reduce the burden of malaria in first pregnancy.

Allelic variants of full-length VAR2CSA, the placental malaria vaccine candidate, differ in antigenicity and receptor binding affinity

Plasmodium falciparum-infected erythrocytes (IE) sequester in the placenta via surface protein VAR2CSA, which binds chondroitin sulfate A (CSA) expressed on the syncytiotrophoblast surface, causing placental malaria (PM) and severe adverse outcomes in mothers and their offspring. VAR2CSA belongs to the PfEMP1 variant surface antigen family; PfEMP1 proteins mediate IE adhesion and facilitate parasite immunoevasion through antigenic variation. Here we produced deglycosylated (native-like) and glycosylated versions of seven recombinant full-length VAR2CSA ectodomains and compared them for antigenicity and adhesiveness. All VAR2CSA recombinants bound CSA with nanomolar affinity, and plasma from Malian pregnant women demonstrated antigen-specific reactivity that increased with gravidity and trimester. However, allelic and glycosylation variants differed in their affinity to CSA and their serum reactivities. Deglycosylated proteins (native-like) showed higher CSA affinity than glycosylated proteins for all variants except NF54. Further, the gravidity-related increase in serum VAR2CSA reactivity (correlates with acquisition of protective immunity) was absent with the deglycosylated form of atypical M200101 VAR2CSA with an extended C-terminal region. Our findings indicate significant inter-allelic differences in adhesion and seroreactivity that may contribute to the heterogeneity of clinical presentations, which could have implications for vaccine design.

PfEMP1-specific IgG reactivity among Beninese pregnant women with sickle cell trait

Background Sickle cell trait (HbAS) protects against severe Plasmodium falciparum malaria, but not against placental malaria (PM). In this study, PfEMP1-specific antibodies were measured in HbAA and HbAS Beninese pregnant women as a proxy of exposure to specific PfEMP1 variants. Methods Plasma samples collected at delivery from 338 HbAA and 63 HbAS women were used to measure IgG levels to six recombinant PfEMP1 proteins and three corresponding native proteins expressed on the infected erythrocyte (IE) surface. IgG-mediated inhibition of VAR2CSA + IEs adhesion to CSA was also tested. Results Levels of PfEMP1-specific IgG were similar in the two groups, except for native IT4VAR09 on IEs, where IgG levels were significantly higher in HbAS women. Adjusted odds ratios for women with positive IgG to HB3VAR06 and PFD1235w suggest a lower risk of infection with these virulent variants among HbAS individuals. The percentage of IEs binding to CSA did not differ between HbAA and HbAS women, but correlated positively with levels of anti-VAR2CSA and parity. Women with PM had lower levels of anti-VAR2CSA-specific IgG and lower IgG-mediated inhibition of IE adhesion to CSA. Conclusions The findings support similar malaria exposure in HbAA and HbAS women and a lack of HbAS-dependent protection against placental infection among pregnant women.

Malaria in Pregnancy: From Placental Infection to Its Abnormal Development and Damage

Malaria remains a global health burden with Plasmodium falciparum accounting for the highest mortality and morbidity. Malaria in pregnancy can lead to the development of placental malaria, where P. falciparum-infected erythrocytes adhere to placental receptors, triggering placental inflammation and subsequent damage, causing harm to both mother and her infant. Histopathological studies of P. falciparum-infected placentas revealed various placental abnormalities such as excessive perivillous fibrinoid deposits, breakdown of syncytiotrophoblast integrity, trophoblast basal lamina thickening, increased syncytial knotting, and accumulation of mononuclear immune cells within intervillous spaces. These events in turn, are likely to impair placental development and function, ultimately causing placental insufficiency, intrauterine growth restriction, preterm delivery and low birth weight. Hence, a better understanding of the mechanisms behind placental alterations and damage during placental malaria is needed for the design of effective interventions. In this review, using evidence from human studies and murine models, an integrated view on the potential mechanisms underlying placental pathologies in malaria in pregnancy is provided. The molecular, immunological and metabolic changes in infected placentas that reflect their responses to the parasitic infection and injury are discussed. Finally, potential models that can be used by researchers to improve our understanding on the pathogenesis of malaria in pregnancy and placental pathologies are presented.

Myeloperoxidase and Other Markers of Neutrophil Activation Associate With Malaria and Malaria/HIV Coinfection in the Human Placenta

IntroductionPlacental malaria (PM) is characterized by accumulation of inflammatory leukocytes in the placenta, leading to poor pregnancy outcomes. Understanding of the underlying mechanisms remains incomplete. Neutrophils respond to malaria parasites by phagocytosis, generation of oxidants, and externalization of Neutrophil Extracellular Traps (NETs). NETs drive inflammation in malaria but evidence of NETosis in PM has not been reported. Neutrophil activity in the placenta has not been directly investigated in the context of PM and PM/HIV-co-infection.MethodsUsing peripheral and placental plasma samples and placental tissue collected from Kenyan women at risk for malaria and HIV infections, we assessed granulocyte levels across all gravidities and markers of neutrophil activation, including NET formation, in primi- and secundigravid women, by ELISA, western blot, immunohistochemistry and immunofluorescence.ResultsReduced peripheral blood granulocyte numbers are observed with PM and PM/HIV co-infection in association with increasing parasite density and placental leukocyte hemozoin accumulation. In contrast, placental granulocyte levels are unchanged across infection groups, resulting in enhanced placental: peripheral count ratios with PM. Within individuals, PM- women have reduced granulocyte counts in placental relative to peripheral blood; in contrast, PM stabilizes these relative counts, with HIV coinfection tending to elevate placental counts relative to the periphery. In placental blood, indicators of neutrophil activation, myeloperoxidase (MPO) and proteinase 3 (PRTN3), are significantly elevated with PM and, more profoundly, with PM/HIV co-infection, in association with placental parasite density and hemozoin-bearing leukocyte accumulation. Another neutrophil marker, matrix metalloproteinase (MMP9), together with MPO and PRTN3, is elevated with self-reported fever. None of these factors, including the neutrophil chemoattractant, CXCL8, differs in relation to infant birth weight or gestational age. CXCL8 and MPO levels in the peripheral blood do not differ with infection status nor associate with birth outcomes. Indicators of NETosis in the placental plasma do not vary with infection, and while structures consistent with NETs are observed in placental tissue, the results do not support an association with PM.ConclusionsGranulocyte levels are differentially regulated in the peripheral and placental blood in the presence and absence of PM. PM, both with and without pre-existing HIV infection, enhances neutrophil activation in the placenta. The impact of local neutrophil activation on placental function and maternal and fetal health remains unclear. Additional investigations exploring how neutrophil activation and NETosis participate in the pathogenesis of malaria in pregnant women are needed.

PREVALENCE OF PLACENTAL INFECTION WITH PLASMODIUM FALCIPARUM DETECTED BY POLYMERASE CHAIN REACTION AND ASSOCIATED RISK FACTORS IN WOMEN AFTER DELIVERED OUAGADOUGOU (BURKINA FASO)

Background:Malaria is known to have a negative impact on pregnant women and their foetuses. This infection during pregnancy represents a major public health problem in tropical and subtropical regions. The aim of this study was to determine the prevalence and risk factor of Plasmodium falciparum in pregnant women the city of Ouagadougou (Burkina Faso). Methods:A cross-sectional study was conducted from April 2019 to March 2020 in four health districts within Ouagadougou, capital city. Samples were collected from the placenta from 531 women after delivered Plasmodium falciparum then by PCR. Results: The prevalence placental malaria with of Plasmodium falciparum was estimated at 7.53%. The status of unemployment and/ or the status of residence around the city of Ouagadougou represent risk of malaria infection. Conclusion:Malaria in pregnancy is responsible for several complications so emphasis should be placed on communication about malaria control in pregnancy and, the behavior of pregnant women and health workers as well.

Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study

Background Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring. Methods and findings Between April 2014 and April 2015, we followed 421 Malawian mother–baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur–Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], −7.53 [−13.04, −2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], −8.57 [−13.09, −4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies. Conclusions This mother–baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children.

Placental Plasmodium Parasitemia and Pregnancy Outcome In Asymptomatic Parturients at Term In A Tertiary Institution South East Nigeria

Background: Malaria in pregnancy is a major public health problem in sub-Saharan Africa and can result in placental malaria with its associated adverse pregnancy outcomes.Method: This was a case control study involving 190 consenting, asymptomatic, booked parturients, recruited consecutively at 36 week. The aim was to determine the effect of placental malaria on pregnancy outcome in asymptomatic women delivering at term. The participants were screened for malaria parasites using peripheral blood film. Based on their results, the participants were grouped into parasitemia positive cases (Group 1) and parasitemia negative controls (Group 2). Both groups were then followed up in the clinic till they presented in labour at term. In labour, participants’ peripheral venous blood sample were collected and used to determine intrapartum haematocrit and peripheral parasitemia. After delivery, cord blood and a section of the placenta were collected for investigation. Data analysis: Collected data were analysed using Statistical Product and service solutions (SPSS) software (version 20). Numerical variables were presented as mean and standard deviation (Mean SD), while categorical variables were presented as numbers and percentages. Chi-square test(X2) was used to compare qualitative variables. Odds ratio (OR) and Confidence interval(CI) were used to observe the odds of outcomes. A p-value 0.05 was considered statistically significant.Results: The prevalence of placental malaria and congenital malaria were 41.05% and 29.47% respectively. Birth weight, APGAR score, NICU admission or congenital malaria were not statistically significant between the two groups. The mean birth weight was 3.16 ± 0.5 kg while 17.89% had low birth weight. There was also no significant difference between the two groups in terms of the association of placental parasitaemia and maternal anaemia or dose of IPT taken. There was no significant association between placental parasitaemia and low parity. Multivariate logistic regression analysis of maternal anaemia and low birth weight showed significant placental parasitaemia in both cases (p = 0.004). Conclusion: Placental parasitaemia is a major complication of malaria in pregnancy and is associated with adverse feto-maternal effects. Early booking and uptake of intermittent preventive therapy with sulphadoxine-pyrimethamine may help reduce the adverse effects.