Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. METHODS: For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. FINDINGS: We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92). INTERPRETATION: We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted. FUNDING: Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.

Training Community Health Workers to Manage Uncomplicated and Severe Malaria: Experience From 3 Rural Malaria-Endemic Areas in Sub-Saharan Africa.

BACKGROUND: Use of community health workers (CHWs) to increase access to diagnosis and treatment of malaria is recommended by the World Health Organization. The present article reports on training and performance of CHWs in applying these recommendations. METHODS: Two hundred seventy-nine CHWs were trained for 3-5 days in Burkina Faso, Nigeria, and Uganda, and 19 were certified to diagnose and treat only uncomplicated malaria and 235 to diagnose and treat both uncomplicated and severe malaria. Almost 1 year after training, 220 CHWs were assessed using standard checklists using facility staff responses as the reference standard. RESULTS: Training models were slightly different in the 3 countries, but the same topics were covered. The main challenges noticed were the low level of education in rural areas and the involvement of health staff in the supervision process. Overall performance was 98% (with 99% in taking history, 95% in measuring temperature, 85% for measuring respiratory rates, 98% for diagnosis, 98% for classification, and 99% for prescribing treatment). Young, single, new CHWs performed better than their older, married, more experienced counterparts. CONCLUSIONS: Training CHWs for community-based diagnosis and treatment of uncomplicated and severe malaria is possible with basic and refresher training and close supervision of CHWs' performance. CLINICAL TRIALS REGISTRATION: ISRCTRS13858170.

Compliance With Malaria Rapid Diagnostic Testing by Community Health Workers in 3 Malaria-Endemic Countries of Sub-Saharan Africa: An Observational Study.

BACKGROUND: The World Health Organization recommends that all malaria management be based on parasitological identification. We monitored performance of trained community health workers (CHWs) in adhering to this recommendation to restrict artemisinin-based combination therapies (ACTs) to positive rapid diagnostic test (RDT)-confirmed cases in children in 3 malaria-endemic sub-Saharan African countries. METHODS: In 33 villages in Burkina Faso, 45 villages in Nigeria, and 84 villages in Uganda, 265 CHWs were trained over a minimum of 3 days to diagnose malaria using RDTs (prepare, read, record results, and inform the patient about results) and treat RDT-confirmed uncomplicated malaria cases with ACTs. In Nigeria, CHWs were also taught to obtain a thick blood smear. Spent RDT kits and prepared blood slides were collected and interpreted independently in Burkina Faso and Nigeria to confirm CHWs' diagnoses. Interviews were held with 12 of 17 CHWs who prescribed ACTs for patients with RDT-negative test results, and with 16 of 29 caregivers to determine factors related to noncompliance. RESULTS: Of 12 656 patients treated with ACTs in the participating countries (5365 in Burkina Faso, 1648 in Nigeria, and 5643 in Uganda), 29 patients (8 from Burkina Faso, 17 from Nigeria, 4 from Uganda) were RDT negative. The small number of RDT-negative ACT-treated cases limits statistical analysis. Only a few CHWs were involved, and they were more likely to be traders rather than farmers (odds ratio [OR], 6.15; 95% confidence interval [CI], 2.09-18.07; P = .0004). RDT-negative children who were treated with ACTs had a significantly higher probability of residing in a village other than that of the CHW (OR, 3.85; 95% CI, 1.59-9.30; P = .0018). Parental pressure was identified in interviews with parents. CONCLUSIONS: Noncompliance with results of RDT tests is relatively rare when CHWs are trained and well supervised. CLINICAL TRIALS REGISTRATION: ISRCTN13858170.

Malaria Rapid Diagnostic Tests and Malaria Microscopy for Guiding Malaria Treatment of Uncomplicated Fevers in Nigeria and Prereferral Cases in 3 African Countries.

BACKGROUND: The World Health Organization recommends that malaria treatment be based on demonstration of the infecting Plasmodium parasite specie. Malaria rapid diagnostic tests (RDTs) are recommended at community points of care because they are accurate and rapid. We report on parasitological results in a malaria study in selected rural communities in 3 African countries. METHODS: In Nigeria, community health workers (CHWs) performed RDTs (SD-Bioline) and thick blood smears on all children suspected to have malaria. Malaria RDT-positive children able to swallow received artemisinin-based combination therapy (Coartem). In all countries, children unable to take oral drugs received prereferral rectal artesunate irrespective of RDT result and were referred to the nearest health facility. Thick blood smears and RDTs were usually taken at hospital admission. In Nigeria and Burkina Faso, RDT cassettes and blood smears were re-read by an experienced investigator at study end. RESULTS: Trained CHWs enrolled 2148 children in Nigeria. Complete parasitological data of 1860 (86.6%) enrollees were analyzed. The mean age of enrollees was 30.4 ± 15.7 months. The prevalence of malaria parasitemia in the study population was 77.8% (1447/1860), 77.6% (1439/1855), and 54.1% (862/1593) by RDT performed by CHWs vs an expert clinical research assistant vs microscopy (gold standard), respectively. Geometric mean parasite density was 6946/µL (range, 40-436 450/µL). There were 49 cases of RDT false-negative results with a parasite density range of 40-54 059/µL. False-negative RDT results with high parasitemia could be due to non-falciparum infection or result from a prozone effect. Sensitivity and specificity of SD-Bioline RDT results as read by CHWs were 94.3% and 41.6%, respectively, while the negative and positive predictive values were 86.1% and 65.6%, respectively. The level of agreement in RDT reading by the CHWs and experienced research staff was 86.04% and κ statistic of 0.60. The malaria parasite positivity rate by RDT and microscopy among children with danger signs in the 3 countries was 67.9% and 41.8%, respectively. CONCLUSIONS: RDTs are useful in guiding malaria management and were successfully used for diagnosis by trained CHWs. However, false-negative RDT results were identified and can undermine confidence in results and control efforts.

Quantifying and Valuing Community Health Worker Time in Improving Access to Malaria Diagnosis and Treatment.

BACKGROUND: Community health workers (CHWs) are members of a community who are chosen by their communities as first-line, volunteer health workers. The time they spend providing healthcare and the value of this time are often not evaluated. Our aim was to quantify the time CHWs spent on providing healthcare before and during the implementation of an integrated program of diagnosis and treatment of febrile illness in 3 African countries. METHODS: In Burkina Faso, Nigeria, and Uganda, CHWs were trained to assess and manage febrile patients in keeping with Integrated Management of Childhood Illness recommendations to use rapid diagnostic tests, artemisinin-based combination therapy, and rectal artesunate for malaria treatment. All CHWs provided healthcare only to young children usually <5 years of age, and hence daily time allocation of their time to child healthcare was documented for 1 day (in the high malaria season) before the intervention and at several time points following the implementation of the intervention. Time spent in providing child healthcare was valued in earnings of persons with similar experience. RESULTS: During the high malaria season of the intervention, CHWs spent nearly 50 minutes more in daily healthcare provision (average daily time, 30.2 minutes before the intervention vs 79.5 minutes during the intervention; test for difference in means P < .01). On average, the daily time spent providing healthcare during the intervention was 55.8 minutes (Burkina Faso), 77.4 minutes (Nigeria), and 72.2 minutes (Uganda). Using the country minimum monthly salary, CHWs' time allocated to child healthcare for 1 year was valued at US Dollars (USD) $52 in Burkina Faso, USD $295 in Nigeria, and USD $141 in Uganda. CONCLUSIONS: CHWs spend up to an hour and a half daily on child healthcare in their communities. These data are informative in designing reward systems to motivate CHWs to continue providing good-quality services. CLINICAL TRIALS REGISTRATION: ISRCTN13858170.

Feasibility of Malaria Diagnosis and Management in Burkina Faso, Nigeria, and Uganda: A Community-Based Observational Study.

BACKGROUND: Malaria-endemic countries are encouraged to increase, expedite, and standardize care based on parasite diagnosis and treat confirmed malaria using oral artemisinin-based combination therapy (ACT) or rectal artesunate plus referral when patients are unable to take oral medication. METHODS: In 172 villages in 3 African countries, trained community health workers (CHWs) assessed and diagnosed children aged between 6 months and 6 years using rapid histidine-rich protein 2 (HRP2)-based diagnostic tests (RDTs). Patients coming for care who could take oral medication were treated with ACTs, and those who could not were treated with rectal artesunate and referred to hospital. The full combined intervention package lasted 12 months. Changes in access and speed of care and clinical course were determined through 1746 random household interviews before and 3199 during the intervention. RESULTS: A total of 15 932 children were assessed: 6394 in Burkina Faso, 2148 in Nigeria, and 7390 in Uganda. Most children assessed (97.3% [15 495/15 932]) were febrile and most febrile cases (82.1% [12 725/15 495]) tested were RDT positive. Almost half of afebrile episodes (47.6% [204/429]) were RDT positive. Children eligible for rectal artesunate contributed 1.1% of episodes. The odds of using CHWs as the first point of care doubled (odds ratio [OR], 2.15; 95% confidence interval [CI], 1.9-2.4; P < .0001). RDT use changed from 3.2% to 72.9% (OR, 80.8; 95% CI, 51.2-127.3; P < .0001). The mean duration of uncomplicated episodes reduced from 3.69 ± 2.06 days to 3.47 ± 1.61 days, Degrees of freedom (df) = 2960, Student's t (t) = 3.2 (P = .0014), and mean duration of severe episodes reduced from 4.24 ± 2.26 days to 3.7 ± 1.57 days, df = 749, t = 3.8, P = .0001. There was a reduction in children with danger signs from 24.7% before to 18.1% during the intervention (OR, 0.68; 95% CI, .59-.78; P < .0001). CONCLUSIONS: Provision of diagnosis and treatment via trained CHWs increases access to diagnosis and treatment, shortens clinical episode duration, and reduces the number of severe cases. This approach, recommended by the World Health Organization, improves malaria case management. CLINICAL TRIALS REGISTRATION: ISRCTN13858170.

Impact of Improving Community-Based Access to Malaria Diagnosis and Treatment on Household Costs.

BACKGROUND: Community health workers (CHWs) were trained in Burkina Faso, Nigeria, and Uganda to diagnose febrile children using malaria rapid diagnostic tests, and treat positive malaria cases with artemisinin-based combination therapy (ACT) and those who could not take oral medicines with rectal artesunate. We quantified the impact of this intervention on private household costs for childhood febrile illness. METHODS: Households with recent febrile illness in a young child in previous 2 weeks were selected randomly before and during the intervention and data obtained on household costs for the illness episode. Household costs included consultation fees, registration costs, user fees, diagnosis, bed, drugs, food, and transport costs. Private household costs per episode before and during the intervention were compared. The intervention's impact on household costs per episode was calculated and projected to districtwide impacts on household costs. RESULTS: Use of CHWs increased from 35% of illness episodes before the intervention to 50% during the intervention (P < .0001), and total household costs per episode decreased significantly in each country: from US Dollars (USD) $4.36 to USD $1.54 in Burkina Faso, from USD $3.90 to USD $2.04 in Nigeria, and from USD $4.46 to USD $1.42 in Uganda (all P < .0001). There was no difference in the time used by the child's caregiver to care for a sick child (59% before intervention vs 51% during intervention spent ≤2 days). Using the most recent population figures for each study district, we estimate that the intervention could save households a total of USD $29 965, USD $254 268, and USD $303 467, respectively, in the study districts in Burkina Faso, Nigeria, and Uganda. CONCLUSIONS: Improving access to malaria diagnostics and treatments in malaria-endemic areas substantially reduces private household costs. The key challenge is to develop and strengthen community human resources to deliver the intervention, and ensure adequate supplies of commodities and supervision. We demonstrate feasibility and benefit to populations living in difficult circumstances. CLINICAL TRIALS REGISTRATION: ISRCTN13858170.

Pre-referral Rectal Artesunate Treatment by Community-Based Treatment Providers in Ghana, Guinea-Bissau, Tanzania, and Uganda (Study 18): A Cluster-Randomized Trial.

BACKGROUND: If malaria patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate prior to hospital referral can prevent death and disability. The goal is to reduce death from malaria by having rectal artesunate treatment available and used. How best to do this remains unknown. METHODS: Villages remote from a health facility were randomized to different community-based treatment providers trained to provide rectal artesunate in Ghana, Guinea-Bissau, Tanzania, and Uganda. Prereferral rectal artesunate treatment was provided in 272 villages: 109 through community-based health workers (CHWs), 112 via trained mothers (MUMs), 25 via trained traditional healers (THs), and 26 through trained community-chosen personnel (COMs); episodes eligible for rectal artesunate were established through regular household surveys of febrile illnesses recording symptoms eligible for prereferral treatment. Differences in treatment coverage with rectal artesunate in children aged <5 years in MUM vs CHW (standard-of-care) villages were assessed using the odds ratio (OR); the predictive probability of treatment was derived from a logistic regression analysis, adjusting for heterogeneity between clusters (villages) using random effects. RESULTS: Over 19 months, 54 013 children had 102 504 febrile episodes, of which 32% (31 817 episodes) had symptoms eligible for prereferral therapy; 14% (4460) children received treatment. Episodes with altered consciousness, coma, or convulsions constituted 36.6% of all episodes in treated children. The overall OR of treatment between MUM vs CHW villages, adjusting for country, was 1.84 (95% confidence interval [CI], 1.20-2.83; P = .005). Adjusting for heterogeneity, this translated into a 1.67 higher average probability of a child being treated in MUM vs CHW villages. Referral compliance was 81% and significantly higher with CHWs vs MUMs: 87% vs 82% (risk ratio [RR], 1.1 [95% CI, 1.0-1.1]; P < .0001). There were more deaths in the TH cluster than elsewhere (RR, 2.7 [95% CI, 1.4-5.6]; P = .0040). CONCLUSIONS: Prereferral episodes were almost one-third of all febrile episodes. More than one-third of patients treated had convulsions, altered consciousness, or coma. Mothers were effective in treating patients, and achieved higher coverage than other providers. Treatment access was low. CLINICAL TRIALS REGISTRATION: ISRCTN58046240.

Protocol for a drugs exposure pregnancy registry for implementation in resource-limited settings.

BACKGROUND: The absence of robust evidence of safety of medicines in pregnancy, particularly those for major diseases provided by public health programmes in developing countries, has resulted in cautious recommendations on their use. We describe a protocol for a Pregnancy Registry adapted to resource-limited settings aimed at providing evidence on the safety of medicines in pregnancy. METHODS/DESIGN: Sentinel health facilities are chosen where women come for prenatal care and are likely to come for delivery. Staff capacity is improved to provide better care during the pregnancy, to identify visible birth defects at delivery and refer infants with major anomalies for surgical or clinical evaluation and treatment. Consenting women are enrolled at their first antenatal visit and careful medical, obstetric and drug-exposure histories taken; medical record linkage is encouraged. Enrolled women are followed up prospectively and their histories are updated at each subsequent visit. The enrolled woman is encouraged to deliver at the facility, where she and her baby can be assessed. DISCUSSION: In addition to data pooling into a common WHO database, the WHO Pregnancy Registry has three important features: First is the inclusion of pregnant women coming for antenatal care, enabling comparison of birth outcomes of women who have been exposed to a medicine with those who have not. Second is its applicability to resource-poor settings regardless of drug or disease. Third is improvement of reproductive health care during pregnancies and at delivery. Facility delivery enables better health outcomes, timely evaluation and management of the newborn, and the collection of reliable clinical data. The Registry aims to improves maternal and neonatal care and also provide much needed information on the safety of medicines in pregnancy.

Etiology of severe invasive infections in young infants in rural settings in sub-Saharan Africa.

BACKGROUND: Serious invasive infections in newborns are a major cause of death. Lack of data on etiological causes hampers progress towards reduction of mortality. This study aimed to identify pathogens responsible for such infections in young infants in sub-Saharan Africa and to describe their antibiotics resistance profile. METHODS: Between September 2016 and April 2018 we implemented an observational study in two rural sites in Burkina Faso and Tanzania enrolling young infants aged 0-59 days old with serious invasive infection. Blood samples underwent blood culture and molecular biology. RESULTS: In total 634 infants with clinical diagnosis of serious invasive infection were enrolled and 4.2% of the infants had a positive blood culture. The most frequent pathogens identified by blood culture were Klebsiella pneumonia and Staphylococcus aureus, followed by Escherichia coli. Gram-negative isolates were only partially susceptible to first line WHO recommended treatment for neonatal sepsis at community level. A total of 18.6% of the infants were PCR positive for at least one pathogen and Escherichia coli and Staphylococcus aureus were the most common bacteria detected. Among infants enrolled, 60/634 (9.5%) died. Positive blood culture but not positive PCR was associated with risk of death. For most deaths, no pathogen was identified either by blood culture or molecular testing, and hence a causal agent remained unclear. Mortality was associated with low body temperature, tachycardia, respiratory symptoms, convulsions, history of difficult feeding, movement only when stimulated or reduced level of consciousness, diarrhea and/or vomiting. CONCLUSION: While Klebsiella pneumonia and Staphylococcus aureus, as well as Escherichia coli were pathogens most frequently identified in infants with clinical suspicion of serious invasive infections, most cases remain without definite diagnosis, making more accurate diagnostic tools urgently needed. Antibiotics resistance to first line antibiotics is an increasing challenge even in rural Africa.

Can we measure cognitive constructs consistently within and across cultures? Evidence from a test battery in Bangladesh, Ghana, and Tanzania.

We developed a test battery for use among children in Bangladesh, Ghana, and Tanzania, assessing general intelligence, executive functioning, and school achievement. The instruments were drawn from previously published materials and tests. The instruments were adapted and translated in a systematic way to meet the needs of the three assessment contexts. The instruments were administered by a total of 43 trained assessors to 786 children in Bangladesh, Ghana, and Tanzania with a mean age of about 13 years (range: 7-18 years). The battery provides a psychometrically solid basis for evaluating intervention studies in multiple settings. Within-group variation was adequate in each group. The expected positive correlations between test performance and age were found and reliability indices yielded adequate values. A confirmatory factor analysis (not including the literacy and numeracy tests) showed a good fit for a model, merging the intelligence and executive tests in a single factor labeled general intelligence. Measurement weights invariance was found, supporting conceptual equivalence across the three country groups, but not supporting full score comparability across the three countries.

Out-of-pocket costs and other determinants of access to healthcare for children with febrile illnesses: a case-control study in rural Tanzania.

OBJECTIVES: To study private costs and other determinants of access to healthcare for childhood fevers in rural Tanzania. METHODS: A case-control study was conducted in Tanzania to establish factors that determine access to a health facility in acute febrile illnesses in children less than 5 years of age. Carers of eligible children were interviewed in the community; cases were represented by patients who went to a facility and controls by those who did not. A Household Wealth Index was estimated using principal components analysis. A multivariable logistic regression analysis was performed to understand the factors which influenced attendance of healthcare facility including severity of the illness and household wealth/socio-demographic indicators. To complement the data on costs from community interviews, a hospital-based study obtained details of private expenditures for hospitalised children under the age of 5. RESULTS: Severe febrile illness is strongly associated with health facility attendance (OR: 35.76, 95%CI: 3.68-347.43, p = 0.002 compared with less severe febrile illness). Overall, the private costs of an illness for patients who went to a hospital were six times larger than private costs of controls ($5.68 vs. $0.90, p<0.0001). Household wealth was not significantly correlated with total costs incurred. The separate hospital based cost study indicated that private costs were three times greater for admissions at the mission versus public hospital: $13.68 mission vs. $4.47 public hospital (difference $ 9.21 (95% CI: 7.89 -10.52), p<0.0001). In both locations, approximately 50% of the cost was determined by the duration of admission, with each day in hospital increasing private costs by about 12% (95% CI: 5% - 21%). CONCLUSION: The more severely ill a child, the higher the probability of attending hospital. We did not find association between household wealth and attending a health facility; nor was there an association between household wealth and private cost.