Preclinical Trial of Traditional Plant Remedies for the Treatment of Complications of Gestational Malaria

Background: Most pregnant women living in high malaria endemic regions of Nigeria use herbal remedies for the management of malaria-in-pregnancy, rather than the commonly prescribed drugs. Remedies common to this area involve a suspension of A. indica (AI) leaves and in some cases, a suspension containing a mixture of AI and D.edulis (PS). Aim: This study examined the therapeutic efficacies of AI, PS, or a combination of AI and PS in a pregnant rat model for exoerythrocytic stages of Plasmodium falciparum parasite. Method: A predetermined sample size of 30 dams was used (for a power level and confidence interval of 95%), and divided equally into six groups made up of non-malarous dams, untreated malarous dams, and malarous dams either treated exclusively with 1 mL of 3000 mg/kg b.w AI, 1000 mg/kg b.w PS, AI + PS (50% v/v), or 25 mg/kg b.w CQ. Result: No maternal mortality was recorded. AI significantly improved maternal weight gain from 32.4 to 82.2 g and placental weight from 0.44 to 0.53 g. In the curative test, AI and AI + PS significantly reduced the average percentage parasitemia (APP) in the pregnant rats from >80% to <20%. No significant difference in the APP was found between the pregnant rats treated with any of CQ or AI during the suppressive test. Results for the prophylactic test of the study groups showed that the APP was significantly reduced from 24.69% to 3.90% when treated with AI and 3.67% when combined with PS. AI + PS reduced diastolic blood pressure from 89.0 to 81.0 mm/Hg and compared with that of the non malarous dams. AI or AI + PS significantly increased the platelet counts (103 µL) from 214.1 to 364.5 and 351.2, respectively. AI and AI + PS improved birth weight from 2.5 to 3.9 g and crown rump length from 2.6 to 4.1 cm. For biomarkers of preeclampsia, combining AI and PS led to the reversal of the altered levels of creatine kinase, lactate dehydrogenase, cardiac troponin, soluble Fms-Like Tyrosine Kinase-1, and placental growth factor. Conclusions: This study validates the use of A. indica for the treatment of gestational malaria due to its antiplasmodial and related therapeutic effects and in combination with pear seeds for the management of malaria-in-pregnancy-induced preeclampsia.

Glycogenes in Oncofetal Chondroitin Sulfate Biosynthesis are Differently Expressed and Correlated With Immune Response in Placenta and Colorectal Cancer

Oncofetal chondroitin sulfate expression plays an important role in the development of tumors and the pathogenesis of malaria in pregnancy. However, the biosynthesis and functions of these chondroitin sulfates, particularly the tissue-specific regulation either in tumors or placenta, have not been fully elucidated. Here, by examining the glycogenes availability in chondroitin sulfate biosynthesis such as xylosytransferase, chondroitin synthase, sulfotransferase, and epimerase, the conserved or differential CS glycosylation in normal, colorectal cancer (CRC), and placenta tissue were predicted. We found that the expression of seven chondroitin sulfate biosynthetic enzymes, namely B4GALT7, B3GALT6, B3GAT3, CHSY3, CHSY1, CHPF, and CHPF2, were significantly increased, while four other enzymes (XYLT1, CHST7, CHST15, and UST) were decreased in the colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) patients. In the human placenta, where the distinct chondroitin sulfate is specifically bound with VAR2CSA on Plasmodium parasite-infected RBC, eight chondroitin sulfate biosynthesis enzymes (CSGALNACT1, CSGALNACT2, CHSY3, CHSY1, CHPF, DSE, CHST11, and CHST3) were significantly higher than the normal colon tissue. The similarly up-regulated chondroitin synthases (CHSY1, CHSY3, and CHPF) in both cancer tissue and human placenta indicate an important role of the proteoglycan CS chains length for Plasmodium falciparum VAR2CSA protein binding. Interestingly, twelve highly expressed chondroitin sulfate enzymes were significantly correlated to worse outcomes (prognosis) in both COAD and READ. Furthermore, we showed that the levels of chondroitin sulfate enzymes are significantly correlated with the expression of immuno-regulators and immune infiltration levels in CRCs and placenta, and involved in multiple essential pathways, such as extracellular matrix organization, epithelial-mesenchymal transition, and cell adhesion. Our study provides novel insights into the oncofetal chondroitin sulfate biosynthesis regulation and identifies promising targets and biomarkers of immunotherapy for CRC and malaria in pregnancy.

The association between acute fatty liver disease and nitric oxide during malaria in pregnancy

Background Liver disease is a common feature of malaria in pregnancy, but its pathogenesis remains unclear. Methods To understand the pathogenesis of liver disease during malaria in pregnancy, comparative proteomic analysis of the liver in a mouse model of malaria in pregnancy was performed. Results Decreased levels of mitochondrial and peroxisomal proteins were observed in the livers of pregnant mice infected with the lethal rodent malaria parasite Plasmodium berghei strain NK65. By contrast, increased levels of perilipin-2, amyloid A-1, and interferon (IFN)-γ signalling pathway-related proteins were observed in the livers of infected pregnant mice, suggesting that IFN-γ signalling may contribute to the development of liver disease during malaria in pregnancy. IFN-γ signalling is a potential trigger of inducible nitric oxide synthase (iNOS) expression. Liver disease associated with microvesicular fatty infiltration and elevated liver enzymes in pregnant wild-type mice infected with malaria parasites was improved by iNOS deficiency. Conclusions In this study, a causative role of iNOS in liver disease associated with microvesicular fatty infiltration during malaria in pregnancy was demonstrated. These findings provide important insight for understanding the role of iNOS-mediated metabolic responses and the pathogenesis of high-risk liver diseases in pregnancy, such as acute fatty liver.

Using Andersen’s Behavioural Model of Health Services use to Examine usage of Intermittent Preventive Treatment of Malaria in Pregnancy in Nigeria

Background: Studies in Nigeria and elsewhere in sub-Saharan Africa have explored factors influencing usage of intermittent preventive treatment of malaria in pregnancy (IPTp). However, most of the studies are not model or theory-based, which provides less satisfactory guidance to malaria control programming. This study fills the knowledge gap by adapting the Andersen’s behavioural model of health services use to IPTp usage in Nigeria.Methods: This study adopted a cross-sectional design that utilised secondary data extracted from the 2018 Nigeria Demographic and Health Survey (NDHS). A weighted sample of 4,772 women who had deliveries in the past year preceding the survey was analysed. The outcome variable was usage of IPTp dichotomised into optimal or otherwise. The explanatory variables cut across individual and community levels, and were divided into predisposing, enabling and need factors in line with the theoretical constructs of the Andersen model. Two multilevel mixed-effects logistic regression models were fitted to identify the factors influencing optimal usage of IPTp. Analyses were performed using Stata 14. Statistical significance was set at 5%. Results: The realised level of optimal IPTp usage was 21.8%. The factors that either predispose or enables a pregnant woman to take optimal doses of IPTp are age, education, being employed, being autonomous on own healthcare, health insurance enrolment, partner education, receiving antenatal care in public health facility, rural residence, being resident in northern geo-political zones, community literacy level, and community perception of the consequences of malaria. Two significant need factors affecting optimal usage of IPTp are timing of first antenatal care contact and actual sleeping under mosquito bed net. Conclusion: Optimal usage of IPTp is low among pregnant women in Nigeria. There is need to devise additional public health education programme promoting IPTp usage through the formation of Advocacy, Communication and Social Mobilisation (ACSM) core group in every ward in all the local government areas in the country. In addition, health planners in the country should adopt the use of the Andersen model for assessing key determinants of IPTp usage among childbearing women in the country.

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.

Epidemiology of Malaria in Pregnancy and Associated Risk Factors in Nigeria: a Review

Each year, an estimated number of 300–500 million people are infected with malaria parasite, with an undesirable effect of over one million deaths. Pregnant women as well as young children, non-immune travellers visiting malaria-endemic zones are at the highest risk of suffering or experiencing life - threatening malaria infection. Maternal immunity, parasite density, parity, inadequate antenatal care services, drug misuse and abuse as well intermitted preventive treatment drug failure cum resistance are the most associated risk factors of malaria in pregnancy obtainable in endemic regions of sub-Saharan Africa. Identification and understanding of these factors will play a major role in reducing the burden as well as eliminating malaria disease among pregnant women living in endemic regions.

A Cluster Randomized Trial of Delivery of Intermittent Preventive Treatment of Malaria in Pregnancy at the Community Level in Malawi

Background Malaria in pregnancy doubles the risk of low birthweight and causes 11% of all neonatal deaths in sub-Saharan Africa. To prevent these and other adverse health consequences, the World Health Organization recommends administering intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine–pyrimethamine for all pregnant women at each antenatal care (ANC) visit, starting as early as possible in the second trimester. The target is for countries to administer a minimum of three doses (IPTp3+) to at least 85% of pregnant women. Methods A cluster randomized, controlled trial was conducted to assess the effect of delivery of IPTp by community health workers on the coverage of IPTp3+ and ANC visits in Malawi. Community delivery of IPTp was implemented within two districts in Malawi over a 21-month period, from November 2018 to July 2020. In control sites, IPTp was delivered at health facilities. Representative samples of women who delivered in the prior 12 months were surveyed at baseline (n=370, December 2017) and endline (n=687, August 2020). A difference in differences analysis was conducted to assess the change in coverage of IPTp and ANC over time, accounting for clustering at the health facility level. Results Overall IPTp coverage increased over the study period. At baseline, women received a mean of 2.3 IPTp doses (range 0–5 doses) across both arms, and at endline, women received a mean of 2.8 doses (range 0–9 doses). Despite overall increases, the change in IPTp3+ coverage was not significantly different between intervention and control groups (6.9%, 95% CI: -5.9%, 19.6%). ANC4+ coverage increased significantly in the intervention group compared with the control group, with a difference-in-differences of 25.3 percentage points (95% CI: 1.3%, 49.3%). Conclusions In order to reduce the burden of malaria in pregnancy, new strategies are needed to improve uptake of effective interventions such as IPTp. While community health workers’ delivery of IPTp did not increase uptake in this study, they may be effective in other settings or circumstances. Further research can help identify the health systems characteristics that are conducive to community delivery of IPTp and the operational requirements for effective implementation. Trial registration: ClinicalTrials.gov Identifier: NCT03376217. Registered December 6, 2017, https://clinicaltrials.gov/ct2/show/NCT03376217

Using the Problem Tree and Results Chain to Improve Uptake of Intermittent Preventive Treatment in Pregnancy Services—Case Study of the Malaria Action Program for Districts in Uganda

Malaria in pregnancy contributes considerably to poor pregnancy outcomes. The U.S. Agency for International Development’s Malaria Action Program for Districts project in Uganda used the Problem Tree and Results Chain tool to identify demand and supply barriers responsible for the low uptake of intermittent preventive treatment of malaria in pregnancy (IPTp) in 52 districts of Uganda. The key supply-side barriers identified were related to leadership/governance, health financing, medicines and technologies, health information systems, human resources, service delivery, and users. The project used the results to plan and implement interventions targeting the barriers. As a result, from October 2018 to September 2019, the project reported an apparent improvement in uptake of three or more doses of IPTp (49–67%). Malaria in pregnancy cases and stock out of sulfadoxine-pyrimethamine (SP) did not change considerably. The Problem Tree and Results Chain tool is a useful and complementary project management tool to identify root causes and their solutions during planning and implementation. Projects using this tool should periodically re-assess performance of IPTp policy implementation and develop appropriate solutions to address the key bottlenecks identified to increase the likelihood of sustained improvement. Further evaluation of the utility of the tool in other settings is recommended.