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.

Pharmacokinetic Study of Rectal Artesunate in Children with Severe Malaria in Africa.

When severe malaria is suspected in children, the WHO recommends pretreatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, crossover clinical trial in 82 Congolese children with severe falciparum malaria to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg of body weight) followed 12 h later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at 11 fixed intervals, following 0- and 12-h drug administrations. Clinical, laboratory, and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large interindividual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients, however, reached previously suggested in vivo IC50 and IC90 values (98.7% and 92.5%, respectively) of combined concentrations of artesunate and dihydroartemisinin between 15 and 30 min after drug administration. The median (interquartile range [IQR]) time above IC50 and IC90 was 5.68 h (2.90 to 6.08) and 2.74 h (1.52 to 3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7 to 54.5) for artesunate and 19.8% (10.3 to 35.3) for dihydroartemisinin. The initial 12-h parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR), 84.3% (50.0 to 95.4) versus 69.2% (45.7 to 93.6), respectively (P = 0.49). Despite large interindividual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria while they are transferred to a facility where parenteral artesunate is available. (This study has been registered at ClinicalTrials.gov under identifier NCT02492178.).

Ceftriaxone Absorption Enhancement for Noninvasive Administration as an Alternative to Injectable Solutions.

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop noninjectable formulations that can reduce treatment delays in resource-limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via nonparenteral administration. This article presents all available data on the nonparenteral absorption of ceftriaxone in humans and animals, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new data from preclinical studies with rabbits, and discusses the importance of these data for the development of noninjectable formulations for noninvasive treatment. The combined results indicate that the rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, chenodeoxycholate sodium salt (Na-CDC), used as an absorption enhancer at a 125-mg dose, together with a 500-mg dose of ceftriaxone provided 24% rectal absorption of ceftriaxone and a maximal plasma concentration of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for the bioavailability of other formulations before assessment in humans.

Household costs and time to treatment for children with severe febrile illness in rural Burkina Faso: the role of rectal artesunate.

BACKGROUND: Community health workers (CHWs) were trained to identify children with malaria who could not take oral medication, treat them with rectal artesunate (RA) and refer them to the closest healthcare facility to complete management. However, many children with such symptoms did not seek CHWs' care. The hypothesis was that the cost of referral to a health facility was a deterrent. The goal of this study was to compare the out-of-pocket costs and time to seek treatment for children who sought CHW care (and received RA) versus those who did not. METHODS: Children with symptoms of severe malaria receiving RA at CHWs and children with comparable disease symptoms who did not go to a CHW were identified and their parents were interviewed. Household out-of-pocket costs per illness episode and speed of treatment were evaluated and compared between RA-treated children vs. non-RA treated children and by central nervous symptoms (CNS: repeated convulsions, altered consciousness or coma). RESULTS: Among children with CNS symptoms, costs of RA-treated children were similar to those of non-RA treated children ($5.83 vs. $4.65; p = 0.52), despite higher transport costs ($2.74 vs. $0.91; p < 0.0001). However, among children without CNS symptoms, costs of RA-treated children were higher than the costs of non-RA treated children with similar symptoms ($5.62 vs. $2.59; p = 0.0001), and the main driver of the cost difference was transport. After illness onset, CNS children reached CHWs for RA an average of 9.0 h vs. 16.1 h for non-RA treated children reaching first treatment [difference 7.1 h (95% CI - 1.8 to 16.1), p = 0.11]. For non-CNS patients the average time to CHW-delivered RA treatment was 12.2 h vs. 20.1 h for those reaching first treatment [difference 7.9 h (95% CI 0.2-15.6), p = 0.04]. More non-RA treated children developed CNS symptoms before arrival at the health centre but the difference was not statistically significant (6% vs. 4%; p = 0.58). CONCLUSIONS: Community health worker-delivered RA does not affect the total out-of-pocket costs when used in children with CNS symptoms, but is associated with higher total out-of-pocket costs when used in children with less severe symptoms. RA-treated children sought treatment more quickly.

Protected to death: systematic exclusion of pregnant women from Ebola virus disease trials.

BACKGROUND: For 30 years, women have sought equal opportunity to be included in trials so that drugs are equitably studied in women as well as men; regulatory guidelines have changed accordingly. Pregnant women, however, continue to be excluded from trials for non-obstetric conditions, though they have been included for trials of life-threatening diseases because prospects for maternal survival outweighed potential fetal risks. Ebola virus disease is a life-threatening infection without approved treatments or vaccines. Previous Ebola virus (EBOV) outbreak data showed 89-93% maternal and 100% fetal/neonatal mortality. Early in the 2013-2016 EBOV epidemic, an expert panel pointed to these high mortality rates and the need to prioritize and preferentially allocate unregistered interventions in favor of pregnant women (and children). Despite these recommendations and multiple ethics committee requests for their inclusion on grounds of justice, equity, and medical need, pregnant women were excluded from all drug and vaccine trials in the affected countries, either without justification or on grounds of potential fetal harm. An opportunity to offer pregnant women the same access to potentially life-saving interventions as others, and to obtain data to inform their future use, was lost. Once again, pregnant women were denied autonomy and their right to decide. CONCLUSION: We recommend that, without clear justification for exclusion, pregnant women are included in clinical trials for EBOV and other life-threatening conditions, with lay language on risks and benefits in information documents, so that pregnant women can make their own decision to participate. Their automatic exclusion from trials for other conditions should be questioned.

Ethics review of studies during public health emergencies - the experience of the WHO ethics review committee during the Ebola virus disease epidemic.

BACKGROUND: Between 2013 and 2016, West Africa experienced the largest ever outbreak of Ebola Virus Disease. In the absence of registered treatments or vaccines to control this lethal disease, the World Health Organization coordinated and supported research to expedite identification of interventions that could control the outbreak and improve future control efforts. Consequently, the World Health Organization Research Ethics Review Committee (WHO-ERC) was heavily involved in reviews and ethics discussions. It reviewed 24 new and 22 amended protocols for research studies including interventional (drug, vaccine) and observational studies. WHO-ERC REVIEWS: WHO-ERC provided the reviews within on average 6 working days. The WHO-ERC often could not provide immediate approval of protocols for reasons which were not Ebola Virus Disease specific but related to protocol inconsistencies, missing information and complex informed consents. WHO-ERC considerations on Ebola Virus Disease specific issues (benefit-risk assessment, study design, exclusion of pregnant women and children from interventional studies, data and sample sharing, collaborative partnerships including international and local researchers and communities, community engagement and participant information) are presented. CONCLUSIONS: To accelerate study approval in future public health emergencies, we recommend: (1) internally consistent and complete submissions with information documents in language participants are likely to understand, (2) close collaboration between local and international researchers from research inception, (3) generation of template agreements for data and sample sharing and use during the ongoing global consultations on bio-banks, (4) formation of Joint Scientific Advisory and Data Safety Review Committees for all studies linked to a particular intervention or group of interventions, (5) formation of a Joint Ethics Review Committee with representatives of the Ethics Committees of all institutions and countries involved to strengthen reviews through the different perspectives provided without the 'opportunity costs' for time to final approval of multiple, independent reviews, (6) direct information exchange between the chairs of advisory, safety review and ethics committees, (7) more Ethics Committee support for investigators than is standard and (8) a global consultation on criteria for inclusion of pregnant women and children in interventional studies for conditions which put them at particularly high risk of mortality or other irreversible adverse outcomes under standard-of-care.

Compliance With Referral Advice After Treatment With Prereferral Rectal Artesunate: A Study in 3 Sub-Saharan African Countries.

BACKGROUND: Children aged <5 years were enrolled in a large study in 3 countries of sub-Saharan Africa because they had danger signs preventing them from being able to take oral medications. We examined compliance and factors associated with compliance with referral advice for those who were treated with rectal artesunate. METHODS: Patient demographic data, speed of accessing treatment after danger signs were recognized, clinical symptoms, malaria microscopy, treatment-seeking behavior, and compliance with referral advice were obtained from case record forms of 179 children treated with prereferral rectal artesunate in a multicountry study. We held focus group discussions and key informant interviews with parents, community health workers (CHWs), and facility staff to understand the factors that deterred or facilitated compliance with referral advice. RESULTS: There was a very high level of compliance (90%) among patients treated with prereferral rectal artesunate. Age, symptoms at baseline (prostration, impaired consciousness, convulsions, coma), and malaria status were not related to referral compliance in the analysis. CONCLUSIONS: Teaching CHWs to diagnose and treat young children with prereferral rectal artesunate is feasible in remote communities of Africa, and high compliance with referral advice can be achieved.

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.

Motivation of Community Health Workers in Diagnosing, Treating, and Referring Sick Young Children in a Multicountry Study.

BACKGROUND: Community health workers (CHWs) are an important element of care provision for a wide range of conditions, but their turnover rate is high. Many studies have been conducted on health workers' motivation, focusing on formal sector staff but not CHWs. Although CHWs are easy to recruit, motivating and retaining them for service delivery is difficult. This article investigates factors influencing CHW motivation and retention in health service delivery. METHODS: Quantitative and qualitative data were collected to identify the key factors favoring motivation and retention of CHWs as well as those deterring them. We interviewed 47, 25, and 134 CHWs in Burkina Faso, Nigeria, and Uganda, respectively, using a structured questionnaire. Focus group discussions (FGDs) were also conducted with CHWs, community participants, and facility health workers. RESULTS: Except for Burkina Faso, most CHWs were female. Average age was between 38 and 41 years, and most came from agricultural communities. The majority (52%-80%) judged they had a high to very high level of satisfaction, but most CHWs (approximately 75%) in Burkina Faso and Uganda indicated that they would be prepared to leave the job, citing income as a major reason. Community recognition and opportunities for training and supervision were major incentives in all countries, but the volume of unremunerated work, at a time when both malaria-positive cases and farming needs were at their peak, was challenging. CONCLUSIONS: Most CHWs understood the volunteer nature of their position but desired community recognition and modest financial remuneration. CLINICAL TRIALS REGISTRATION: ISRCTN13858170.

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.

Exposure to artemether-lumefantrine (Coartem) in first trimester pregnancy in an observational study in Zambia.

BACKGROUND: In general, safety data following exposure to drugs in the first trimester of pregnancy are scarce. More specifically, data on the safety of artemisinin-based combination therapy (ACT) in pregnancy still remain limited. Therefore, pregnant women from Choma, Zambia, who were exposed to artemether-lumefantrine (AL) for the treatment of uncomplicated malaria were followed up and evaluated in a prospective cohort study. This report assessed the longitudinal safety outcomes of the pregnant women inadvertently exposed during the first trimester. METHODS: Participants were classified based on the drug used to treat their most recent malaria episode: artemether-lumefantrine (AL) versus sulphadoxine-pyrimethamine (SP) and/or quinine. All enrolled women were followed up until six weeks post-delivery and the live births for 12 months. RESULTS: There were 294 first trimester exposures in the observational cohort (pregnant women: AL = 150, AL and SP = 9 and SP and/or quinine = 135). Similar rates of perinatal mortality (stillbirths and neonatal deaths) were observed for each treatment arm (AL 4.4%, SP and/or quinine 3.9%). At delivery (newborns: AL = 135, AL and SP = 7 and SP and/or quinine = 129), the gestational age (measured using the Dubowitz total scores), length and head circumference of the newborns were similar between the two arms. Low birth weights were reported in 10.2% (95% CI 6.0, 16.6) and 6.7% (95% CI 3.4, 12.6) of newborns in the AL and SP and/or quinine arms, respectively. Overall development (including neurodevelopmental parameters) was similar between the two arms, both at 14 weeks and 12 months of age. CONCLUSION: Exposure to AL and SP in the first trimester was not associated with particular safety risks such as perinatal mortality, preterm deliveries or low birth weights. Such outcomes as well as infant neurodevelopmental parameters up to 12 months were similar between the two arms. These findings add to the body of data suggesting that randomized clinical trials could now be the way forward to assess safety and efficacy of ACT in the first trimester of pregnancy.

Introducing the concept of a new pre-referral treatment for severely ill febrile children at community level: a sociological approach in Guinea-Bissau.

BACKGROUND: Innovative strategies are needed to tackle childhood mortality in the rural tropics. Artesunate suppositories were developed to bring emergency treatment closer to severely ill children with malaria in rural areas where injectable treatment is not possible for several hours. Adding an antibacterial rectal drug would extend this strategy to treat non-malarial febrile illness as well. The objective of these studies was to assess acceptability of such a new pre-referral strategy by healthcare providers and likely uptake by the population. METHODS: Two qualitative studies were conducted between May and July 2009. Study 1 investigated the acceptability of introducing a combined antimalarial-antibacterial suppository by interviewing 27 representatives of the three administrative levels (central government, regional, local) of the health sector; Study 2 investigated treatment-seeking behaviour and acceptability of this intervention at community level by interviewing 74 mothers in 2 villages. RESULTS AND CONCLUSIONS: Up to 92% of health representatives were in favour of introducing a new pre-referral strategy to tackle both malaria and non-malaria related severe illnesses in Guinea-Bissau, provided it was endorsed by international health authorities. The main obstacles to implementation were the very limited human and financial resources. In the two villages surveyed, 44% of the mothers associated severe illness with fever only, or fever plus one additional symptom. Mothers' judgement of severity and ensuing decisions were not specific for serious illness, indicating that initial training to recognize signs of severe disease and treatment availability for non-severe, fever-associated symptoms will be required to prevent overuse of a new intervention designed as a pre-referral treatment for severely ill children. Level C health centres were the first resort in both villages (50% and 87% of respondents respectively). This information is encouraging for the implementation of a pre-referral treatment.

Influences on participant reporting in the World Health Organisation drugs exposure pregnancy registry; a qualitative study.

BACKGROUND: The World Health Organisation has designed a pregnancy registry to investigate the effect of maternal drug use on pregnancy outcomes in resource-limited settings. In this sentinel surveillance system, detailed health and drug use data are prospectively collected from the first antenatal clinic visit until delivery. Over and above other clinical records, the registry relies on accurate participant reports about the drugs they use. Qualitative methods were incorporated into a pilot registry study during 2010 and 2011 to examine barriers to women reporting these drugs and other exposures at antenatal clinics, and how they might be overcome. METHODS: Twenty-seven focus group discussions were conducted in Ghana, Kenya and Uganda with a total of 208 women either enrolled in the registry or from its source communities. A question guide was designed to uncover the types of exposure data under- or inaccurately reported at antenatal clinics, the underlying reasons, and how women prefer to be asked questions. Transcripts were analysed thematically. RESULTS: Women said it was important for them to report everything they had used during pregnancy. However, they expressed reservations about revealing their consumption of traditional, over-the-counter medicines and alcohol to antenatal staff because of anticipated negative reactions. Some enrolled participants' improved relationship with registry staff facilitated information sharing and the registry tools helped overcome problems with recall and naming of medicines. Decisions about where women sought care, which influenced medicines used and antenatal clinic attendance, were influenced by pressure within and outside of the formal healthcare system to conform to conflicting behaviours. Conversations also reflected women's responsibilities for producing a healthy baby. CONCLUSIONS: Women in this study commonly take traditional medicines in pregnancy, and to a lesser extent over-the-counter medicines and alcohol. The World Health Organisation pregnancy registry shows potential to enhance their reporting of these substances at the antenatal clinic. However, more work is needed to find optimal techniques for eliciting accurate reports, especially where the detail of constituents may never be known. It will also be important to find ways of sustaining such drug exposure surveillance systems in busy antenatal clinics.

A study to validate the Ten-Question-Questionnaire + for the detection of moderate to severe neurological disabilities in older Bangladeshi children.

PURPOSE: Our study validated the Ten Question Questionnaire (TQQ+) for Bangladeshi children between 10 and 16 years. The TQQ + is a rapid screening tool for disability and was previously validated in children below 9 years of age. MATERIALS AND METHODS: The study was carried out in Chattogram, Bangladesh. One hundred children aged 10-16 years, 10 with mild or moderate disabilities, 40 with severe disabilities, and 50 children without a disability were identified. Children with disability (n = 50) had previously undergone Wechsler Intelligence Scale-Revised (WISC-R) assessments by psychologists as a reference standard. Each child was evaluated using Rapid Neurodevelopmental Assessment (RNDA) by physicians and TQQ + was administered by researchers. Sensitivities and specificities of TQQ + were evaluated in comparison with RNDA and WISC-R. RESULTS: The sensitivity of TQQ + was 98% in comparison with either RNDA or WISC-R. The specificity of TQQ was 76.5% compared with RNDA and 78% with WISC-R. TQQ + successfully picked up cognitive (98%) and motor (75%) disabilities as well as behavioural problems (88.9%). Specificity was good to excellent in all other domains. Logistic regression showed that TQQ + could reliably predict disability by RNDA and WISC-R. The area under the Receiver Operating Characteristic Curve (ROC) curve was 0.88 which denoted good diagnostic accuracy of the questionnaire. CONCLUSION: The TQQ + is valid for screening disabilities in 10-16 year old Bangladeshi children.IMPLICATIONS FOR REHABILITATIONIf children with neurodevelopmental disabilities are screened early, the benefit of intervention will be greater.TQQ + is an easy to administer and low-cost tool that has been validated internationally.The TQQ + is now validated and can be used for children aged 10 to 16 years in Bangladesh.