Management of severe malaria: challenges and lessons learned with the introduction of pre-referral Rectal Artesunate in the Democratic Republic of the Congo

Malaria causes over 240 million cases and over 600,000 deaths annually, mostly among children under the age of five years. The Democratic Republic of the Congo (DRC) has the second highest malaria mortality in the world, accounting for 12% of the global burden of malaria. Despite substantial improvements in prevention and treatment during the past 10 years, malaria remains the principal cause of morbidity and mortality, accounting for 44% of all deaths among outpatient visits in children, and 22% of all in-patient deaths. One of the major challenges in severe malaria case management remains the limited access to higher-level health facilities where a full treatment can be provided. This is especially an issue for populations living in remote areas, resulting in treatment delays of several hours or even days. In such situations, the World Health Organization (WHO) recommends pre-referral treatment, either with a single dose of a parenteral anti-malarial, or with a single dose of rectal artesunate (RAS). The Congolese National Malaria Control Programme (NMCP) is committed to reducing the high number of malaria-related deaths through proven interventions such as pre-referral RAS. The aim of this thesis was to identify challenges and draw lessons learned from the implementation of pre-referral RAS in DRC, in view of supporting its responsible introduction into the national health system. The present work was entirely conducted in the frame of the multi-country Community Access to Rectal Artesunate for Malaria (CARAMAL) project. In DRC, we setup a patient surveillance system (PSS) in three Health Zones to determine the distribution of dangers signs for severe malaria and assess their impact on RAS use, referral completion, injectable treatment and ACT provision, and health outcomes including death. To contextualize the data gathered through the PSS, we also conducted cross-sectional household surveys in the same locations to assess treatment seeking predictors and the prevalence of malaria. Findings showed a high prevalence of malaria (45.1%, 95% CI 39.8–50.4) and anaemia (79.5%, 95% CI 77.1–81.7) in these communities. The presence of danger signs was not optimal but still increased the likelihood of seeking treatment (aOR=2.12, 95% CI 1.03–4.38). Unfortunately, still many children with danger signs were not brought to health facilities, or were brought late. Importantly, danger signs were well recognized by health provider at the primary care level, and RAS is acceptable and can be given without problem by low-level health care workers. Referral Health Facilities (RHF) are the subsequent point of contact for severely ill children, after they successfully complete their referral. According to the current treatment recommendations, the post-referral treatment of severe malaria comprises the provision of parenteral artesunate for at least 24 hours, followed by a full course of an Artemisinin Combination Therapy (ACT) once the patient can tolerate oral medication. In the RHFs, our aim was to assess the compliance of health care workers with the recommended treatment in children under 5 years. While only half of children were given parenteral antimalarial treatment (50.3%, 2,117/4,208), inpatient ACT administration was more common (78.7%, 1,314/1,669). The overall poor quality of severe malaria case management at higher-level facilities is an important health system issue and it is probably the reasons why the introduction of RAS did not have an impact on the Case Facility Rate of the pediatric patients. In addition, parenteral artesunate not followed up with oral ACT constitutes an artemisinin monotherapy and may favor the selection of resistant parasites. Stricter compliance with the WHO severe malaria treatment guidelines is critical to effectively manage this disease and further reduce child mortality. Finally, we assessed the health system costs and constraints to the successful implementation of pre-referral RAS at community level. We did so to inform operational guidance and financial planning for the scale-up of RAS as pre-referral treatment for severe malaria. The equivalent annual costs of preparing the health system for managing severe malaria with RAS was $4.19 per child at risk, and$464 per child treated. Strengthening essential routine health system components accounted for the majority of these costs (76.4%). In conclusion, introducing pre-referral RAS as a single intervention seemed not to add value in terms of reducing child mortality. Deploying successful pre-referral RAS at large scale requires preceding investments to strengthen the health system along the entire cascade of care. Only then can the potential of RAS as a pre-referral treatment be realized

Safety of daily low-dose aspirin use during pregnancy in low-income and middle-income countries

Background: The daily use of low-dose aspirin may be a safe, widely available, and inexpensive intervention for reducing the risk of preterm birth. Data on the potential side effects of low-dose aspirin use during pregnancy in low- and middle-income countries are needed.Objective: This study aimed to assess differences in unexpected emergency medical visits and potential maternal side effects from a randomized, double-blind, multicountry, placebo-controlled trial of low-dose aspirin use (81 mg daily, from 6 to 36 weeks\u27 gestation).Study design: This study was a secondary analysis of data from the Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial, a trial of the Global Network for Women\u27s and Children\u27s Health conducted in India (2 sites), Pakistan, Guatemala, Democratic Republic of the Congo, Kenya, and Zambia. The outcomes for this analysis were unexpected emergency medical visits and the occurrence of the following potential side effects-overall and separately-nausea, vomiting, rash or hives, diarrhea, gastritis, vaginal bleeding, allergic reaction, and any other potential side effects. Analyses were performed overall and by geographic region.Results: Between the aspirin (n=5943) and placebo (n=5936) study groups, there was no statistically significant difference in the risk of unexpected emergency medical visits or the risk of any potential side effect (overall). Of the 8 potential side effects assessed, only 1 (rash or hives) presented a different risk by treatment group (4.2% in the aspirin group vs 3.5% in the placebo group; relative risk, 1.20; 95% confidence interval, 1.01-1.43; P=.042).Conclusion: The daily use of low-dose aspirin seems to be a safe intervention for reducing the risk of preterm birth and well tolerated by nulliparous pregnant women between 6 and 36 weeks\u27 gestation in low- and middle-income countries

Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation. METHODS: ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks\u27 gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970. FINDINGS: From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks\u27 gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (\u3c34 \u3eweeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups. INTERPRETATION: In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Safety of daily low-dose aspirin use during pregnancy in low-income and middle-income countries

BACKGROUND The daily use of low-dose aspirin may be a safe, widely available, and inexpensive intervention for reducing the risk of preterm birth. Data on the potential side effects of low-dose aspirin use during pregnancy in low- and middle-income countries are needed. OBJECTIVE This study aimed to assess differences in unexpected emergency medical visits and potential maternal side effects from a randomized, double-blind, multicountry, placebo-controlled trial of low-dose aspirin use (81 mg daily, from 6 to 36 weeks’ gestation). STUDY DESIGN This study was a secondary analysis of data from the Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial, a trial of the Global Network for Women's and Children's Health conducted in India (2 sites), Pakistan, Guatemala, Democratic Republic of the Congo, Kenya, and Zambia. The outcomes for this analysis were unexpected emergency medical visits and the occurrence of the following potential side effects—overall and separately—nausea, vomiting, rash or hives, diarrhea, gastritis, vaginal bleeding, allergic reaction, and any other potential side effects. Analyses were performed overall and by geographic region. RESULTS Between the aspirin (n=5943) and placebo (n=5936) study groups, there was no statistically significant difference in the risk of unexpected emergency medical visits or the risk of any potential side effect (overall). Of the 8 potential side effects assessed, only 1 (rash or hives) presented a different risk by treatment group (4.2% in the aspirin group vs 3.5% in the placebo group; relative risk, 1.20; 95% confidence interval, 1.01–1.43; P=.042). CONCLUSION The daily use of low-dose aspirin seems to be a safe intervention for reducing the risk of preterm birth and well tolerated by nulliparous pregnant women between 6 and 36 weeks’ gestation in low- and middle-income countries

Cost-Effectiveness of Low-Dose Aspirin for the Prevention of Preterm Birth: A Prospective Study of the Global Network for Women’s and Children’s Health Research

Background: Premature birth is associated with an increased risk of mortality and morbidity, and strategies to prevent preterm birth are few in number and resource intensive. In 2020, the ASPIRIN trial showed the efficacy of low-dose aspirin (LDA) in nulliparous, singleton pregnancies for the prevention of preterm birth. We sought to investigate the cost-effectiveness of this therapy in low-income and middle-income countries. Methods: In this post-hoc, prospective, cost-effectiveness study, we constructed a probabilistic decision tree model to compare the benefits and costs of LDA treatment compared with standard care using primary data and published results from the ASPIRIN trial. In this analysis from a health-care sector perspective, we considered the costs and effects of LDA treatment, pregnancy outcomes, and neonatal health-care use. We did sensitivity analyses to understand the effect of the price of the LDA regimen, and the effectiveness of LDA in reducing both preterm birth and perinatal death. Findings: In model simulations, LDA was associated with 141 averted preterm births, 74 averted perinatal deaths, and 31 averted hospitalisations per 10 000 pregnancies. The reduction in hospitalisation resulted in a cost of US$248 per averted preterm birth,$471 per averted perinatal death, and $15·95 per disability-adjusted life year. Interpretation: LDA treatment in nulliparous, singleton pregnancies is a low-cost, effective treatment to reduce preterm birth and perinatal death. The low cost per disability-adjusted life year averted strengthens the evidence in support of prioritising the implementation of LDA in publicly funded health care in low-income and middle-income countries. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Cost-Effectiveness of Low-Dose Aspirin for the Prevention of Preterm Birth: A Prospective Study of the Global Network for Women\u27s and Children\u27s Health Research

Background: Premature birth is associated with an increased risk of mortality and morbidity, and strategies to prevent preterm birth are few in number and resource intensive. In 2020, the ASPIRIN trial showed the efficacy of low-dose aspirin (LDA) in nulliparous, singleton pregnancies for the prevention of preterm birth. We sought to investigate the cost-effectiveness of this therapy in low-income and middle-income countries. Methods: In this post-hoc, prospective, cost-effectiveness study, we constructed a probabilistic decision tree model to compare the benefits and costs of LDA treatment compared with standard care using primary data and published results from the ASPIRIN trial. In this analysis from a health-care sector perspective, we considered the costs and effects of LDA treatment, pregnancy outcomes, and neonatal health-care use. We did sensitivity analyses to understand the effect of the price of the LDA regimen, and the effectiveness of LDA in reducing both preterm birth and perinatal death. Findings: In model simulations, LDA was associated with 141 averted preterm births, 74 averted perinatal deaths, and 31 averted hospitalisations per 10 000 pregnancies. The reduction in hospitalisation resulted in a cost of US$248 per averted preterm birth,$471 per averted perinatal death, and $15·95 per disability-adjusted life year. Interpretation: LDA treatment in nulliparous, singleton pregnancies is a low-cost, effective treatment to reduce preterm birth and perinatal death. The low cost per disability-adjusted life year averted strengthens the evidence in support of prioritising the implementation of LDA in publicly funded health care in low-income and middle-income countries. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Assessing caregivers’ perceptions of treatment-seeking for suspected severe malaria in the Democratic Republic of the Congo

Abstract Background Malaria remains a major public health issue in the Democratic Republic of the Congo (DRC), accounting for 44% deaths among outpatient visits in children < 5 years of age, and 22% of facility deaths. Understanding determinants of caregivers’ treatment-seeking patterns and decision-making is crucial in reducing the malaria burden. Methods In the frame of the Community Access to Rectal Artesunate for Malaria (CARAMAL) project, cross-sectional household surveys that randomly sampled villages and households were carried-out in three rural DRC health zones prior to the rollout of pre-referral Rectal Artesunate (RAS) and then 9 and 19 months after RAS rollout (post-RAS). Data were captured electronically through face-to-face interviews with the main caregivers of children < 5 years. Capillary blood samples of the children were tested for malaria and anaemia. The main study outcome was whether caregiver “sought treatment outside home” when the child had fever. Multilevel mixed effects logistic regression models using village as random effect and health zone as a fixed effect was performed to assess treatment-seeking predictors. Results 2439 household interviews were completed (pre-RAS 888 and post-RAS 1551), including 316 and 653 treatment-seeking interviews. Overall, 3499 children < 5 years were tested for malaria and anaemia (pre-RAS 1,315 and post-RAS 2184). Caregiver’s recognition of severe malaria signs was poor, while knowledge of symptoms of uncomplicated malaria seemed high. Despite this, danger signs significantly increased the odds of seeking treatment (aOR = 2.12, 95%CI 1.03–4.38), the same was found for the “least poor” quintile (aOR = 3.01, 95%CI 1.03–8.82), as well as residents of Kingandu (aOR = 2.78, 95%CI 1.01–7.65). “Doing something at home” against fever negatively affected treatment-seeking in both study phases. RAS acceptance was high, at almost 100%. Malaria prevalence was higher post-RAS (45.2%) compared to pre-RAS (34.4%), p = 0.003, but anaemia, although high (≥ 75%), was similar in both study phases (p = 0.92). Conclusion In remote communities with high malaria prevalence in the DRC, malaria remains a major problem. Improving the recognition of danger signs of severe disease and introducing pre-referral RAS may improve treatment-seeking and contribute to reducing malaria-related mortality among children—if quality of care can be guaranteed

Additional file 1 of Assessing caregivers’ perceptions of treatment-seeking for suspected severe malaria in the Democratic Republic of the Congo

Additional file 1: Figure S1. Sampling flow-charts. Figure S2. Main sources of outside treatment visited by caregivers in baseline and midline surveys. Baseline (N = 97). Midline (N = 91). CHW = Community Health Worker. PHC = Primary health care facilities. RHF = Referral Health facilities

The impact of risk factors on aspirin\u27s efficacy for the prevention of preterm birth

Background: The ASPIRIN Trial was a landmark study that demonstrated a reduction in preterm birth (PTB) and hypertensive disorders of pregnancy (HDP) in nulliparous women who received low-dose aspirin (LDA). All women in the study had at least one moderate-risk factor for preeclampsia, nulliparity. Unlike current United States Preventative Service Task Force (USPSTF) guidelines, which recommend LDA for two or more moderate-risk factors, women in this study were randomized to receive LDA regardless of the presence or absence of an additional risk factor. Objective: To compare how low-dose aspirin (LDA) differentially benefits nulliparous women with and without additional preeclampsia risk factors for the prevention of preterm birth (PTB) and hypertensive disorders of pregnancy (HDP). Study design: This is a non-pre-specified secondary analysis of the ASPIRIN trial that randomized nulliparous women with singleton pregnancies from six low-middle income countries to receive LDA or placebo. Our primary exposure was having an additional preeclampsia risk-factor beyond nulliparity. Our primary outcome was PTB before 37 weeks and our secondary outcomes included PTB before 34 weeks, PTB before 28 weeks, HDP, and perinatal mortality. Results: Among 11,558 nulliparous women who met the inclusion criteria, 66.8% had no additional risk factors. LDA similarly reduced the risk of PTB (RR 0.75 vs. 0.85, p=0.35). Additionally for our secondary outcomes, LDA similarly reduced the risk of PTB \u3c28 \u3eweeks, HDP, and perinatal mortality in women with and without additional risk factors. The reduction of PTB (RR 0.69 vs. 1.04, p=0.04). Conclusion: LDA\u27s ability to prevent PTB, HDP, and perinatal mortality is similar in nulliparous women with and without additional risk factors. Professional societies should consider recommending LDA to all nulliparous wome

Association of hemoglobin levels in the first trimester and at 26 to 30 weeks with fetal and neonatal outcomes: A secondary analyses of the global network for women\u27s and children\u27s health\u27s ASPIRIN trial

Objective: Limited data are available from low- and middle-income countries (LMICs) on the relationship of hemoglobin (HGB) levels at different times in pregnancy to adverse outcomes. We evaluated the association of HGB levels in nulliparous women at two times in pregnancy with pregnancy outcomes.Design: ASPIRIN Trial data were used to study the association between HGB levels measured at 6+0 to 13+6 weeks and 26+0 to 30+0 weeks gestational age (GA) with fetal and neonatal outcomes.Setting: Obstetric care facilities in Pakistan, India, Kenya, Zambia, The Democratic Republic of the Congo and Guatemala POPULATION: 11,976 pregnant women METHODS: Generalized linear models were used to obtain adjusted relative risks and 95% CI for adverse outcomes.Main outcome measures: Preterm birth, stillbirth, neonatal death, SGA and birth weight \u3c2500 grams.Results: The mean HGB at 6+0 -13+6 weeks GA and at 26-30 weeks GA were 116 g/L (sd 17) and 107 g/L (sd 15) respectively. In general, pregnancy outcomes were better with increasing HGB. At 6+0 -13+6 weeks GA, stillbirth, SGA and birth weight \u3c2500 g, were significantly associated with HGB of 70-89 g/L as compared to HGB of 110-129 g/L The relationships of adverse pregnancy outcomes with various HGB levels were more marked at 26-30 weeks of GA.Conclusions: Both lower and some higher HGB concentrations are associated with adverse fetal and neonatal outcomes at 6+0 -13+6 weeks and at 26-30 weeks GA, although the relationship with low HGB levels appears more consistent and generally stronger