Malaria In Pregnancy Research Articles

Malaria in pregnancy in India: a 50-year bird's eye.

In 2021, India contributed for ~79% of malaria cases and ~ 83% of deaths in the South East Asia region. Here, we systematically and critically analyzed data published on malaria in pregnancy (MiP) in India. Epidemiological, clinical, parasitological, preventive and therapeutic aspects of MiP and its consequences on both mother and child were reviewed and critically analyzed. Knowledge gaps and solution ways are also presented and discussed. Several electronic databases including Google scholar, Google, PubMed, Scopus, Wiley Online library, the Malaria in Pregnancy Consortium library, the World Malaria Report, The WHO regional websites, and ClinicalTrials.gov were used to identify articles dealing with MiP in India. The archives of local scientific associations/journals and website of national programs were also consulted. Malaria in pregnancy is mainly due to Plasmodium falciparum (Pf) and P. vivax (Pv), and on rare occasions to P. ovale spp. and P. malariae too. The overall prevalence of MiP is ~0.1-57.7% for peripheral malaria and ~ 0-29.3% for placental malaria. Peripheral Pf infection at antenatal care (ANC) visits decreased from ~13% in 1991 to ~7% in 1995-1996 in Madhya Pradesh, while placental Pf infection at delivery unit slightly decreased from ~1.5% in 2006-2007 to ~1% in 2012-2015 in Jharkhand. In contrast, the prevalence of peripheral Pv infection at ANC increased from ~1% in 2006-2007 to ~5% in 2015 in Jharkhand, and from ~0.5% in 1984-1985 to ~1.5% in 2007-2008 in Chhattisgarh. Clinical presentation of MiP is diverse ranging from asymptomatic carriage of parasites to severe malaria, and associated with comorbidities and concurrent infections such as malnutrition, COVID-19, dengue, and cardiovascular disorders. Severe anemia, cerebral malaria, severe thrombocytopenia, and hypoglycemia are commonly seen in severe MiP, and are strongly associated with tragic consequences such as abortion and stillbirth. Congenital malaria is seen at prevalence of ~0-12.9%. Infected babies are generally small-for-gestational age, premature with low birthweight, and suffer mainly from anemia, thrombocytopenia, leucopenia and clinical jaundice. Main challenges and knowledge gaps to MiP control included diagnosis, relapsing malaria, mixed Plasmodium infection treatment, self-medication, low density infections and utility of artemisinin-based combination therapies. All taken together, the findings could be immensely helpful to control MiP in malaria endemic areas.

Prevalence of molecular markers of resistance to sulfadoxine–pyrimethamine before and after community delivery of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa: a multi-country evaluation

The effectiveness of community delivery of intermittent preventive treatment (C-IPT) of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine has been evaluated in selected areas of the Democratic Republic of the Congo, Madagascar, Mozambique, and Nigeria. We aimed to assess the effect of C-IPTp on the potential development of Plasmodium falciparum resistance to sulfadoxine-pyrimethamine, since it could threaten the effectiveness of this strategy. Health facility-based cross-sectional surveys were conducted at baseline and 3 years after C-IPTp implementation in two neighbouring areas per country, one with C-IPTp intervention, and one without, in the four project countries. Dried blood spots from children under five years of age with clinical malaria were collected. Sulfadoxine-pyrimethamine resistance-associated mutations of the P falciparum dhfr (Asn51Ile/Cys59Arg/Ser108Asn/Ile164Leu) and dhps (Ile431Val/Ser436Ala/Ala437Gly/Lys540Glu/Ala581Gly/Ala613Ser) genes were analysed. 2536 children were recruited between June 19 and Oct 10, 2018, during baseline surveys. Endline surveys were conducted among 2447 children between July 26 and Nov 30, 2021. In the Democratic Republic of the Congo, the dhfr/dhps IRNI/ISGEAA inferred haplotype remained lower than 10%, from 2% (5 of 296) at baseline to 8% (24 of 292) at endline, and from 3% (9 of 300) at baseline to 6% (18 of 309) at endline surveys in intervention and non-intervention areas respectively with no significant difference in the change between the areas. In Mozambique, the prevalence of this haplotype remained stable at over 60% (194 [64%] of 302 at baseline to 194 [64%] of 303 at endline, and 187 [61%] of 306 at baseline to 183 [61%] of 301 in endline surveys, in non-intervention and intervention areas respectively). No isolates harbouring the dhps ISGEAA genotype were found in Nigeria. In Madagascar, only five isolates with this haplotype were found in the non-intervention area (2 [>1%] of 300 at baseline and 3 [1%] of 300 at endline surveys). No isolates were found carrying the dhps ISGEGA genotype. C-IPTp did not increase the prevalence of molecular markers associated with sulfadoxine-pyrimethamine resistance after three years of programme implementation. These findings reinforce C-IPTp as a strategy to optimise the control of malaria during pregnancy, and support the WHO guidelines for prevention of malaria in pregnancy. UNITAID [2017-13-TIPTOP].

Intestinal barrier disruption with Plasmodium falciparum infection in pregnancy and risk of preterm birth: a cohort study

Malaria in early pregnancy is a risk factor for preterm birth and is associated with sustained inflammation and dysregulated angiogenesis across gestation. This study investigated whether malaria is associated with increased gut leak and whether this contributes to systemic inflammation, altered angiogenesis, and preterm birth. We quantified plasma concentrations of gut leak markers, soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) from 1339 HIV-negative pregnant Malawians at <24 weeks gestational age. We assessed the relationship of sCD14 and LBP concentrations with markers of inflammation, angiogenesis, and L-arginine bioavailability and compared them between participants with and without malaria, and with and without preterm birth. Plasma concentrations of sCD14 and LBP were significantly higher in participants with malaria and were associated with parasite burden (p <0.0001, both analyses and analytes). The odds ratio for preterm birth associated with one log sCD14 was 2.67 (1.33 to 5.35, p=0.006) and 1.63 (1.07-2.47, p=0.023) for LBP. Both gut leak analytes were positively associated with increases in proinflammatory cytokines CRP, sTNFR2, IL18-BP, CHI3L1 and Angptl3 (p <0.05, all analytes) and sCD14 was significantly associated with angiogenic proteins Angpt-2, sENG and the sFLT:PlGF ratio (p <0.05, all analytes). sCD14 was negatively associated with L-arginine bioavailability (p <0.001). Malaria in early pregnancy is associated with intestinal barrier dysfunction, which is linked to an increased risk of preterm birth. Open Philanthropy, Canadian Institutes of Health Research, Canada Research Chair program, European and Developing Countries Clinical Trials Partnership, Bill & Melinda Gates Foundation.

Urinalysis, Malaria Random Diagnostic Methods and Clinical Symptoms in the Prediction of Malaria Parasitaemia among Pregnant Women in Umuahia and Ikwuano, Abia State, Nigeria

This study was targeted at assessing malaria prevalence, clinical symptoms and urine abnormalities associated with malaria in pregnancy. A cross-sectional study involving 250 pregnant women selected from five healthcare facilities in three local government areas of Abia state, was conducted. Data were collected using pre-tested structured questionnaires and patients’ blood and urine samples collected. Thick and thin blood films microscopy as well as malaria random kits were used to diagnose malaria. Medi-test combi 9 urine test strip was used to check urine abnormalities. Data were analysed using SPSS version 26. An overall malaria prevalence of 56% (95% CI: 0.42-0.60) was observed. Of the five centres, the highest prevalence was reported at PHC III in Umuahia North LGA with prevalence at 72% (95% CI: 0.51-0.98), while the lowest was reported at PHC IV in Umuahia North LGA with a prevalence of 36% (95% CI: 0.21-0.49). Pregnant women who had headache (OR=3.316, p=0.009, 95% CI: 1.288-7. 400), catarrh (OR=3.972, p=0.032, 95% CI: 1.028-15.352) and fever (OR=9.459, p&lt;0.001, 95% CI: 3.767-23.753) had higher odds of malaria infection, compared to those without headache, catarrh and fever. Malaria was largely recorded among the primigravids 71% (53/75), followed by the secundigravidae 61% (43/70) and the least, observed among the multigravidae 43% (45/105). High malaria prevalence was observed among subjects who did not use preventive measures (100%) with the least observed among subjects, using window nets (22%). Malaria among subjects in this study is significantly prevalent. Proteinuria, bilirubinuria, urobilinogenuria as well as amber and clear urine macroscopy showed significant associations with malaria in pregnancy; thus, women with these clinical features should be further tested for malaria even in asymptomatic states to prevent the negative consequences of malaria in pregnancy.

Social determination of malaria in pregnancy in Colombia: a critical ethnographic study

BackgroundThe meanings and experiences related to malaria in pregnancy (MiP) and its processes of social determination of health (PSDH) have not been reported in the world scientific literature. The objective was to understand the meanings and experiences of MiP, and to explain their PSDH in an endemic area from Colombia, 2022.MethodsCritical ethnography with 46 pregnant women and 31 healthcare workers. In-depth and semi-structured interviews, focus group discussions, participant and non-participant observations, and field diaries were applied. A phenomenological-hermeneutic analysis, saturation and triangulation was carried out. The methodological rigor criteria were reflexivity, credibility, auditability, and transferability.ResultsAt the singular level, participants indicated different problems in antenatal care and malaria control programmes, pregnant women were lacking knowledge about MiP, and malaria care was restricted to cases with high obstetric risk. Three additional levels that explain the PSDH of MiP were identified: (i) limitations of malaria control policies, and health-system, geographic, cultural and economic barriers by MiP diagnosis and treatment; (ii) problems of public health programmes and antenatal care; (iii) structural problems such as monetary poverty, scarcity of resources for public health and inefficiency in their use, lacking community commitment to preventive actions, and breach of institutional responsibilities of health promoter entity, municipalities and health services provider institutions.ConclusionInitiatives for MiP control are concentrated at the singular level, PDSH identified in this research show the need to broaden the field of action, increase health resources, and improve public health programmes and antenatal care. It is also necessary to impact the reciprocal relationships of MiP with economic and cultural dimensions, although these aspects are increasingly diminished with the predominance and naturalization of neoliberal logic in health.

FRI492 Malaria In Pregnancy And Lipopolyssacharide Lead To Sex-specific Changes In The Expression Of Genes Involved In The Placental Metabolism Of Thyroid Hormones

Abstract Disclosure: K.N. Fontes: None. V.S. Monteiro: None. C.B. Andrade: None. A.C. Valim: None. V.M. Nascimento: None. D.E. Teixeira: None. A.A. Pinheiro: None. E. Bloise: None. T.M. Ortiga-Carvalho: None. Infection during gestation promotes marked changes in placental physiology, leading to intrauterine growth restriction (IUGR), preterm labor (PTL) and neurodevelopmental disorders. Infection in pregnant women or mice may impact thyroid hormones’ (TH) metabolism and the importance of TH for the development of the placenta and conceptus is widely described in the literature. Our main aim was to evaluate changes in the expression of specific genes involved in placental TH metabolism triggered by malaria in pregnancy (MiP) or bacterial lipopolyssacharide (LPS), in the male and female placenta. Female C57BL/6 mice (8-10 weeks of age) were mated. In the MiP model, dams were infected ip with Plasmodium Berghei ANKA-infected erythrocytes (PBA; 5x105 infected-erythrocytes, n=10) or injected with PBS (contro; n=10) at gestational day (GD)13.5 and sacrificed at GD18.5. In the LPS model, dams were injected ip with LPS (150 µg/kg, n=10) or PBS (control; n=10) at GD17.5 and sacrificed at GD18.5. Maternal blood was collected to evaluate PBA parasitemia. Placental disks were collected from dams delivering at term (GD18.5), and qPCR was performed to evaluate the mRNA expression of genes involved in placental TH metabolism. MiP was confirmed by analysis of parasitemia (15.9%), and resulted in increased maternal spleen weight (P&amp;lt;0.05). As expected, MiP induced PTL (at GD17.5) in 23.1% of dams. Fetal weight and fetal/placental weight ratio were reduced in MiP (at term), compared to control (P&amp;lt;0.05). In the LPS model, 33.3% of dams went into PTL (at GD17.5) and fetal weight was reduced in LPS group (at term), compared to control (P&amp;lt;0.05). In both models, mRNA of the Cxcl1 chemokine (P&amp;lt;0.05) was increased in the male and female placenta at term (P&amp;lt;0.05). Male MiP placentas exhibited a reduction in Slc7a8 (P&amp;lt;0.05) and Dio2 (P&amp;lt;0.05) mRNA expression, whereas female MiP placentas exhibited a reduction in Slc7a8 (P&amp;lt;0.05) and an increase in Slco1c1 and Dio1 (P&amp;lt;0.05) at term. LPS increased Dio1 (P&amp;lt;0.05) mRNA in the male term placenta, and increased Ccl2 (P&amp;lt;0.05) mRNA in the term female placenta. In the present study, MiP was associated with sex-specific changes in the placental expression of TH transporters and deiodinases, while LPS injection promoted a limited effect on placental TH metabolism, but increased the expression of placental inflammatory markers at term. We speculate that these changes may result in reduced TH transport from mother to fetus, leading to IUGR among surviving fetuses, especially in pregnancies threatened by MiP. Presentation: Friday, June 16, 2023

Malaria and Pregnancy.

Recent identification of local mosquito-borne transmission of malaria in Florida, Texas, and Maryland and increasing travel to malaria-endemic countries raise the likelihood that U.S. obstetricians might encounter a pregnant patient with malaria. Pregnancy increases the risk of becoming infected with malaria and of developing severe disease. Malaria during pregnancy also increases the risk of adverse pregnancy outcomes, including low birth weight, pregnancy loss, and preterm birth; thus, prevention and prompt diagnosis and treatment are essential. Diagnosis can be challenging during pregnancy among persons with partial immunity because placental sequestration of parasite-infected red blood cells can result in lower parasite levels in peripheral blood. Treatment for uncomplicated malaria depends on the expected resistance pattern, which is determined by the specific Plasmodium species identified and where infection was acquired. For severe disease, parenteral artesunate treatment needs to be initiated immediately. Given the dire consequences of malaria in pregnancy, prevention is crucial. For persons born and raised in endemic areas, interventions include use of insecticide-treated bed nets, intermittent preventive treatment, and prompt diagnosis and treatment of illness. U.S. pregnant persons should avoid travel to endemic countries; for unavoidable travel, pregnant travelers should receive chemoprophylaxis and avoid mosquito bites. Although the risk is low to U.S. pregnant persons who are not traveling internationally, avoiding mosquito bites is important, especially for pregnant persons residing in or visiting areas with recent local mosquito-borne transmission.

Associations between prenatal malaria exposure, maternal antibodies at birth, and malaria susceptibility during the first year of life in Burkina Faso.

In this study, we investigated how different categories of prenatal malaria exposure (PME) influence levels of maternal antibodies in cord blood samples and the subsequent risk of malaria in early childhood in a birth cohort study (N = 661) nested within the COSMIC clinical trial (NCT01941264) in Burkina Faso. Plasmodium falciparum infections during pregnancy and infants' clinical malaria episodes detected during the first year of life were recorded. The levels of maternal IgG and IgG1-4 to 15 P. falciparum antigens were measured in cord blood by quantitative suspension array technology. Results showed a significant variation in the magnitude of maternal antibody levels in cord blood, depending on the PME category, with past placental malaria (PM) more frequently associated with significant increases of IgG and/or subclass levels across three groups of antigens defined as pre-erythrocytic, erythrocytic, and markers of PM, as compared to those from the cord of non-exposed control infants. High levels of antibodies to certain erythrocytic antigens (i.e., IgG to EBA140 and EBA175, IgG1 to EBA175 and MSP142, and IgG3 to EBA140 and MSP5) were independent predictors of protection from clinical malaria during the first year of life. By contrast, high levels of IgG, IgG1, and IgG2 to the VAR2CSA DBL1-2 and IgG4 to DBL3-4 were significantly associated with an increased risk of clinical malaria. These findings indicate that PME categories have different effects on the levels of maternal-derived antibodies to malaria antigens in children at birth, and this might drive heterogeneity to clinical malaria susceptibility in early childhood.

Perceptions and drivers of healthcare provider and drug dispenser practices for the treatment of malaria in pregnancy in the context of multiple first-line therapies in western Kenya: a qualitative study

BackgroundEmergence of Plasmodium falciparum resistance to artemether-lumefantrine in Africa prompted the pilot introduction of multiple first-line therapies (MFT) against malaria in Kenya, potentially exposing women-of-childbearing-age (WOCBAs) to anti-malarials with unknown safety profiles in the first trimester. This qualitative study explored knowledge and perceptions among healthcare providers providing malaria treatment to WOCBAs and pregnant women.MethodsIn-depth interviews were conducted with purposively selected public and private health facility (HF) and drug outlet (DO) providers within and outside the pilot-MFT area. County health managers were interviewed about their knowledge of the national treatment guidelines. Transcripts were coded by content analysis using the World Health Organization health system building blocks (leadership/governance, financing, health workforce, health information systems, access to medicines, and service delivery).ResultsThirty providers (HF:21, DO:9) and three health managers were interviewed. Eighteen providers were from HFs in the pilot-MFT area; the remaining three and all nine DOs were outside the pilot-MFT area. The analysis revealed that providers had not been trained in malaria case management in the previous twelve months. DO providers were unfamiliar with national treatment guidelines in pregnancy and reported having no pregnancy tests. Health managers were unable to supervise DOs due to resource limitations. Providers from HFs and DOs noted poor sensitivity of malaria rapid diagnostic tests (RDTs) and hesitancy among patients who associated malaria-RDTs with HIV testing. Almost all providers reported anti-malarial stock-outs, with quinine most affected. Patient preference was a major factor in prescribing anti-malarials. Providers in HFs and DOs reported preferentially using artemether-lumefantrine in the first trimester due to the side effects and unavailability of quinine.ConclusionKnowledge of malaria case management in drug outlets and health facilities remains poor. Improved regulation of DO providers is warranted. Optimizing treatment of malaria in pregnancy requires training, availability of malaria commodities, and pregnancy tests.

Healthcare provider and drug dispenser knowledge and adherence to guidelines for the case management of malaria in pregnancy in the context of multiple first-line artemisinin-based combination therapy in western Kenya

BackgroundConcerns about emerging resistance to artemether-lumefantrine (AL) in Africa prompted the pilot introduction of multiple first-line therapies (MFT) in Western Kenya, potentially exposing women-of-childbearing-age (WOCBA) to anti-malarials with unknown safety profiles in the first trimester. The study assessed healthcare provider knowledge and adherence to national guidelines for managing malaria in pregnancy in the context of the MFT pilot.MethodsFrom March to April 2022, a cross-sectional study was conducted in 50 health facilities (HF) and 40 drug outlets (DO) using structured questionnaires to assess pregnancy detection, malaria diagnosis, and treatment choices by trimester. Differences between HF and DO providers and between MFT and non-MFT HFs were assessed using Chi-square tests.ResultsOf 174 providers (77% HF, 23% DO), 56% were from MFT pilot facilities. Most providers had tertiary education; 5% HF and 20% DO had only primary or secondary education. More HF than DO providers had knowledge of malaria treatment guidelines (62% vs. 40%, p = 0.023), received training in malaria in pregnancy (49% vs. 20%, p = 0.002), and reported assessing for pregnancy in WOCBA (98% vs. 78%, p < 0.001). Most providers insisted on parasitological diagnosis, with 59% HF using microscopy and 85% DO using rapid diagnostic tests. More HF than DO providers could correctly name the drugs for treating uncomplicated malaria in the first trimester (oral quinine, or AL if quinine is unavailable) (90% vs. 58%, p < 0.001), second and third trimesters (artemisinin-based combination therapy) (84% vs. 70%, p = 0.07), and for severe malaria (parenteral artesunate/artemether) (94% vs. 60%, p < 0.001). Among HF providers, those in the MFT pilot had more knowledge of malaria treatment guidelines (67% vs. 49%, p = 0.08) and had received training on treatment of malaria in pregnancy (56% vs. 32%, p = 0.03). Few providers (10% HF and 12% DO) had adequate knowledge of malaria treatment in pregnancy, defined as the correct drug and dose for uncomplicated and severe malaria in all trimesters.ConclusionsKnowledge of national malaria in pregnancy treatment guidelines among providers in Western Kenya is suboptimal. Robust training on appropriate anti-malarial and dosage is needed, particularly given the recent change in recommendation for artemether-lumefantrine use in the first trimester. Supervision of DO and HF practices is essential for correct treatment of malaria in pregnancy in the context of MFT programmes.

The question of the early diagnosis of asymptomatic and subpatent malaria in pregnancy: Implications for diagnostic tools in a malaria endemic area.

Malaria in pregnancy (MIP) is a major healthcare challenge in low-income countries with high malaria endemicity. Early but accurate diagnosis and appropriate treatment is the hallmark of preventing disease progression/adverse outcomes in the mother, foetus and neonates. We assessed the comparative diagnostic performance of Malaria Rapid Diagnostic Test (mRDT), microscopy and PCR for malaria diagnosis in pregnant women for early detection of asymptomatic malaria in pregnant women. Five hundred and twenty Pregnant women attending study clinics within Ikene and Remo North LGAs with gestational age between 16 and 29 weeks, willing and consented; were enrolled into the study. Blood samples collected via venepuncture were screened for malaria using microscopy, mRDTs kits, and PCR techniques on their first visit (V1) and at delivery. The parasite positivity rates, sensitivity and specificity were calculated and compared for each technique using PCR as the standard. Data was entered into REDCap® online database and analysis done using Stata and MedCalc®. Average age of enrolled women was 28.8 years and mean gestational age was 21.0 weeks. The parasite positivity rates were 4.3%, 8.8% and 25.0% for microscopy, mRDT and PCR at V1 and was 2.4%, 3.4% and 43.4% at delivery, respectively. Sensitivity for microscopy and mRDT was 11.2% and 30.3% respectively at V1, while specificity was 98.2% and 98.5%. At delivery, the sensitivity reduced to 1.6% and 4.9%; while specificity was 96.9% and 97.6% respectively. Only 2.3% cases correlated with all three diagnostic methods. Our data showed a decrease in sensitivity of the diagnostic methods as pregnancy progressed, which may be due to very low parasitaemia, but high specificity. Our study demonstrated a high rate of subpatent parasitaemia amongst pregnant women. This finding therefore raises the question of the effect of subpatent parasitaemia on the health of the mother and foetus.

Socioecological risk factors associated with Malaria in Pregnancy in an endemic state of India: a retrospective study

IntroductionMalaria in Pregnancy (MiP) has significant adverse effects on both mother and fetus. Pregnant women in regions with unstable malaria transmission are three times more vulnerable to infection. This study...

Malaria in Pregnancy: Key Points for the Neonatologist.

In malaria-endemic regions, infection with the malaria parasite Plasmodium during pregnancy has been identified as a key modifiable factor in preterm birth, the delivery of low-birthweight infants, and stillbirth. Compared with their nonpregnant peers, pregnant persons are at higher risk for malaria infection. Malaria infection can occur at any time during pregnancy, with negative effects for the pregnant person and the fetus, depending on the trimester in which the infection is contracted. Pregnant patients who are younger, in their first or second pregnancy, and those coinfected with human immunodeficiency virus are at increased risk for malaria. Common infection prevention measures during pregnancy include the use of insecticide-treated bed nets and the use of intermittent preventive treatment with monthly doses of antimalarials, beginning in the second trimester in pregnant patients in endemic areas. In all trimesters, artemisinin-combination therapies are the first-line treatment for uncomplicated falciparum malaria, similar to treatment in nonpregnant adults. The World Health Organization recently revised its recommendations, now listing the specific medication artemether-lumefantrine as first-line treatment for uncomplicated malaria in the first trimester. While strong prevention and detection methods exist, use of these techniques remains below global targets. Ongoing work on approaches to treatment and prevention of malaria during pregnancy remains at the forefront of global maternal child health research.

Cord Blood FGF-21 and GDF-15 Levels Are Affected by Maternal Exposure to Moderate to Severe Anemia and Malaria.

Anemia and malaria are global health problems affecting >50% of pregnant women in sub-Saharan Africa and are associated with intrauterine growth restriction. The hormones fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) are involved in metabolic regulation and are expressed in the placenta. No studies exist on FGF-21 and GDF-15 responses to exposures of malaria and anemia in pregnancy. Using a prospective, longitudinal pregnancy and birth cohort of women with an average age of 26 years from a rural region in northeastern Tanzania, we examined if FGF-21 and GDF-15 levels in maternal blood at week 33 ± 2 (n = 301) and in cord blood at birth (n = 353), were associated with anemia and malaria exposure at different time points in pregnancy and with neonatal anthropometry. Among mothers at gestation week 33 ± 2, lower FGF-21 levels were observed after exposure to malaria in the first trimester, but not anemia, whereas GDF-15 levels at week 33 ± 2 were not associated with malaria nor anemia. In cord blood, moderate to severe anemia at any time point in pregnancy was associated with higher levels of FGF-21, whereas malaria exposure in the third trimester was associated with lower FGF-21 levels in cord blood. Negative associations were observed between cord blood FGF-21 and GDF-15 levels and neonatal skinfold thicknesses and birthweight. Our results suggest that moderate to severe anemia throughout pregnancy associates with higher FGF-21 levels, and malaria in last trimester associates with lower FGF-21 levels, in the neonates, thereby potentially affecting the future cardiometabolic health of the child.

Dynamics of Plasmodium berghei NK-65 parasitaemia and CD3+CD4+CD25+Fox-p3+ T-regulatory cells in experimentally induced malaria during early, mid, and late-pregnancy in BALB/c mice.

Malaria in pregnancy causes a dual brunt on the mother as well as the foetus. Upregulation of T-regulatory cells (Tregs) during pregnancy allows tolerance towards the growing foetus, their suppression predisposes the mother to infections. This study analyzed the levels of CD3+CD4+CD25+Fox-p3+ Tregs, parasitaemia, maternal and foetal outcomes in BALB/c mice infected with P. berghei NK65 during early-, mid-, and late-pregnancy. Total of 114 mice, non-pregnant non-infected (n = 6), non-pregnant infected (n = 12), pregnant non-infected (n = 48) and pregnant infected (n = 48) were included in the study. Infected groups were inoculated intra-peritoneally with 1 × 106 P. berghei infected RBCs during early-, mid-, and late- pregnancy (D6, D10, and D14 respectively). Six mice from each stage were sacrificed on the 5th and 7th day post-infection (DPI) to evaluate parasitaemia (staining) and Tregs from splenocytes (by flow cytometry). The parasitaemia was significantly higher among early pregnancy infected mice (≥ 70%) than mid-pregnancy infected (40-70%), late pregnancy infected (50-65%), and non-pregnant infected mice (≤ 50%) (p < 0.05). The level of Tregs was significantly higher among non-pregnant infected mice as compared to non-pregnant non-infected mice (%Tregs 0.86 vs. 0.44). Among pregnant mice, the levels of Tregs in infected mice were lower than in non-infected mice during all stages of pregnancy. None of the mice infected during early- and mid-pregnancy survived at 6DPI and 7DPI, respectively, and those infected during late-pregnancy delivered premature pups. In contrast to non-pregnant mice, the levels of Tregs among pregnant mice decrease when malaria infection is acquired thereby leading to adverse pregnancy outcomes. The online version contains supplementary material available at 10.1007/s12088-023-01089-2.

Malaria-specific Type 1 regulatory T cells are more abundant in first pregnancies and associated with placental malaria

Malaria in pregnancy (MIP) causes higher morbidity in primigravid compared to multigravid women; however, the correlates and mechanisms underlying this gravidity-dependent protection remain incompletely understood. We aimed to compare the cellular immune response between primigravid and multigravid women living in a malaria-endemic region and assess for correlates of protection against MIP. We characterised the second trimester cellular immune response among 203 primigravid and multigravid pregnant women enrolled in two clinical trials of chemoprevention in eastern Uganda, utilizing RNA sequencing, flow cytometry, and functional assays. We compared responses across gravidity and determined associations with parasitaemia during pregnancy and placental malaria. Using whole blood RNA sequencing, no significant differentially expressed genes were identified between primigravid (n=12) and multigravid (n=11) women overall (log 2(FC)>2, FDR < 0.1). However, primigravid (n=49) women had higher percentages of malaria-specific, non-naïve CD4+ T cells that co-expressed IL-10 and IFNγ compared with multigravid (n=85) women (p=0.000023), and higher percentages of these CD4+ T cells were associated with greater risks of parasitaemia in pregnancy (Rs=0.49, p=0.001) and placental malaria (p=0.0073). These IL-10 and IFNγ co-producing CD4+ T cells had a genomic signature of Tr1 cells, including expression of transcription factors cMAF and BATF and cell surface makers CTLA4 and LAG-3. Malaria-specific Tr1 cells were highly prevalent in primigravid Ugandan women, and their presence correlated with a higher risk of malaria in pregnancy. Understanding whether suppression of Tr1 cells plays a role in naturally acquired gravidity-dependent immunity may aid the development of new vaccines or treatments for MIP. This work was funded by NIH (PO1 HD059454, U01 AI141308, U19 AI089674, U01 AI155325, U01 AI150741), the March of Dimes (Basil O'Connor award), and the Bill and Melinda Gates Foundation (OPP 1113682).

Severe falciparum malaria in pregnancy in Southeast Asia: a multi-centre retrospective cohort study

BackgroundSevere malaria in pregnancy causes maternal mortality, morbidity, and adverse foetal outcomes. The factors contributing to adverse maternal and foetal outcomes are not well defined. We aimed to identify the factors predicting higher maternal mortality and to describe the foetal mortality and morbidity associated with severe falciparum malaria in pregnancy.MethodsA retrospective cohort study was conducted of severe falciparum malaria in pregnancy, as defined by the World Health Organization severe malaria criteria. The patients were managed prospectively by the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border or were included in hospital-based clinical trials in six Southeast Asian countries. Fixed-effects multivariable penalised logistic regression was used for analysing maternal mortality.ResultsWe included 213 (123 SMRU and 90 hospital-based) episodes of severe falciparum malaria in pregnancy managed between 1980 and 2020. The mean maternal age was 25.7 (SD 6.8) years, and the mean gestational age was 25.6 (SD 8.9) weeks. The overall maternal mortality was 12.2% (26/213). Coma (adjusted odds ratio [aOR], 7.18, 95% CI 2.01–25.57, p = 0.0002), hypotension (aOR 11.21, 95%CI 1.27–98.92, p = 0.03) and respiratory failure (aOR 4.98, 95%CI 1.13–22.01, p = 0.03) were associated with maternal mortality. Pregnant women with one or more of these three criteria had a mortality of 29.1% (25/86) (95%CI 19.5 to 38.7%) whereas there were no deaths in 88 pregnant women with hyperparasitaemia (> 10% parasitised erythrocytes) only or severe anaemia (haematocrit < 20%) only. In the SMRU prospective cohort, in which the pregnant women were followed up until delivery, the risks of foetal loss (23.3% by Kaplan–Meier estimator, 25/117) and small-for-gestational-age (38.3%, 23/60) after severe malaria were high. Maternal death, foetal loss and preterm birth occurred commonly within a week of diagnosis of severe malaria.ConclusionsVital organ dysfunction in pregnant women with severe malaria was associated with a very high maternal and foetal mortality whereas severe anaemia or hyperparasitaemia alone were not associated with poor prognosis, which may explain the variation of reported mortality from severe malaria in pregnancy. Access to antenatal care must be promoted to reduce barriers to early diagnosis and treatment of both malaria and anaemia.

Complement System Activation Is a Plasma Biomarker Signature during Malaria in Pregnancy.

Malaria in pregnancy (MiP) is a public health problem in malaria-endemic areas, contributing to detrimental outcomes for both mother and fetus. Primigravida and second-time mothers are most affected by severe anemia complications and babies with low birth weight compared to multigravida women. Infected erythrocytes (IE) reach the placenta, activating the immune response by placental monocyte infiltration and inflammation. However, specific markers of MiP result in poor outcomes, such as low birth weight, and intrauterine growth restriction for babies and maternal anemia in women infected with Plasmodium falciparum are limited. In this study, we identified the plasma proteome signature of a mouse model infected with Plasmodium berghei ANKA and pregnant women infected with Plasmodium falciparum infection using quantitative mass spectrometry-based proteomics. A total of 279 and 249 proteins were quantified in murine and human plasma samples, of which 28% and 30% were regulated proteins, respectively. Most of the regulated proteins in both organisms are involved in complement system activation during malaria in pregnancy. CBA anaphylatoxin assay confirmed the complement system activation by the increase in C3a and C4a anaphylatoxins in the infected plasma compared to non-infected plasma. Moreover, correlation analysis showed the association between complement system activation and reduced head circumference in newborns from Pf-infected mothers. The data obtained in this study highlight the correlation between the complement system and immune and newborn outcomes resulting from malaria in pregnancy.

Malaria in pregnancy: adverse pregnancy outcomes and the future of prevention

Malaria in pregnancy (MiP) poses a dangerous health risk to both mothers and their fetuses, causing severe outcomes such as preterm delivery, intrauterine growth restriction, miscarriage, stillbirth, and neonatal and maternal death. Plasmodium falciparum infected erythrocytes sequester in placental intervillous spaces causing placental malaria (PM), eliciting inflammatory responses associated with severe sequelae. Current MiP prevention strategies have improved pregnancy outcomes, but serious morbidity and mortality persist. Vaccines to prevent MiP and PM are under development and are expected to improve pregnancy outcomes. To prepare for safety and efficacy trials of these vaccines, the incidence of adverse pregnancy outcomes including those caused by MiP should be documented at clinical sites. This review summarizes reported key adverse pregnancy outcomes attributable to MiP, providing important baseline context to define measurable safety and efficacy endpoints for malaria vaccine trials in pregnancy.

Malaria-Related Psychosocial Factors, Past Antenatal Care-Seeking Behaviors, and Future Antenatal Care-Seeking Intentions by Maternal Age in Malawi and Democratic Republic of the Congo.

Young women in sub-Saharan Africa are a group at increased risk for malaria in pregnancy. Early antenatal care (ANC) seeking makes it more likely that women will receive the recommended doses of intermittent preventive treatment of malaria in pregnancy. This study used data from national Malaria Behavior Surveys conducted in Malawi and the Democratic Republic of the Congo (DRC) in 2021 to explore the association between intention to attend ANC in the first trimester for a future pregnancy (early ANC intention) and psychosocial factors among women aged 15-49 years. Eight psychosocial factors related to ANC and based on the ideation model were included, including knowledge, attitudes, and self-efficacy. The study used multivariable logistic regression models controlling for demographic characteristics to evaluate associations between early ANC intention and the individual ideational factors and the composite measure. Analysis included 2,148 women aged 15-49 years (Malawi: 827, DRC: 1,321). Antenatal care ideation was lower among young (aged 15-20 years) than among older (aged 21-49 years) women in Malawi. Young mothers with higher ANC ideation were more likely to intend to attend ANC early in their next pregnancy in both countries. Specific ideational factors associated with intention to attend ANC early varied by country and included positive attitudes, knowledge of ANC, and positive self-efficacy. In Malawi and the DRC, youth-friendly social and behavior change interventions to increase ANC-related ideation could increase future early ANC attendance among young women to improve malaria and birth outcomes.