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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.

There are few effective and safe therapeutics for diseases that disproportionally affect impoverished populations, such as malaria and other neglected tropical diseases. But even these few therapeutics would not have [...]

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. 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. 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. The TQQ + is valid for screening disabilities in 10–16 year old Bangladeshi children. If 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. [ABSTRACT FROM AUTHOR]

Introduction The expanding HIV pandemic has had a profound adverse effect on tuberculosis (TB), resulting in a general increase in the burden of TB, increasing the risk of active disease, [...], Over recent years, tuberculosis (TB) and disease caused by human immunodeficiency virus (HIV) have merged in a synergistic pandemic. The number of new cases of TB is stabilizing and declining, except in countries with a high prevalence of HIV infection. In these countries, where HIV is driving an increase in the TB burden, the capacity of the current tools and strategies to reduce the burden has been exceeded. This paper summarizes the current status of TB management and describes recent thinking and strategy adjustments required for the control of TB in settings of high HIV prevalence. We review the information on anti-TB drugs that is available in the public domain and highlight the need for continued and concerted efforts (including financial, human and infrastructural investments) for the development of new strategies and anti-TB agents. Keywords Tuberculosis, Multidrug-resistant/drug therapy; Antitubercular agents/administration and dosage/adverse effects: Directly observed therapy;, Drug therapy/trends; Drug combinations; Quinolones; Quinoline: Nitroimidazoles; Ouinolizines; HIV infections/drug therapy; Evaluation studies (source: MESH, NLM). Mots cles Tuberculose resistante a la polychimiotherapie/chimiotherapie; Antituberculeux/administration et posologie/effets indesirables; Therapie sous observation directe; Chimiotherapie/orientations; Association medicamenteuse; Quinolones; Quinoleines: Nitroimidazoles; Quinolizines; Infection a VIH/chimiotherapie; Etude evaluation (source: MESH, INSERM). Palabras clave Tuberculosis resistente a multidrogas/quimioterapia; Agentes antituberculosos/administracion y dosificacion/efectos adversos; Terapia por observacion directa: Quimioterapia/tendencias; Combinacion de medicamentos; Quinolonas; Quinolinas; Rifamicinas; Nitroimidazoles; Quinolicinas; Infecciones pot VIH/quimioterapia; Estudios de evatuacion (fuente: DeCS, BIREME). Bulletin of the World Health Organization 2005;83:857-865. Voir page 864 le resume an francais. En la pagina 864 figura un resumen an espanol.

The primary objective of malaria control is to reduce deaths and illness from the disease. Elimination of infection is far more difficult. However, in most developing countries where malaria is endemic, there are few reliable data on levels, differences and trends in malaria mortality, and its relative importance as a cause of death or illness in endemic communities. The large-scale efforts and resources being devoted to delivery of essential care to mothers and young children in most countries make it important to have a better understanding of the extent of cause-specific child mortality levels in different epidemiological conditions so that appropriate interventions can be targeted at high risk groups and properly evaluated according to their contribution to mortality reduction. As per capita resources necessary in relation to the scale of the problem remain scarce, governments are finding that they must use their available resources more efficiently in meeting their health objectives. In the case of malaria, there are far too few empirical data documenting the marginal costs and benefits of alternative interventions and their response to an expansion (or contraction) of services, and to the level of endemicity and distribution of disease. Equally important, the literature on private costs of malaria (treatment, transportation etc) provides incomplete guidance to gains from control unless the authors begin to examine the policy implications of their results; for example, in many countries there is accumulating evidence that private expenditures outweigh public expenditures on health. What effect does this mix have on infectious diseases like malaria where public sector expenditures on prevention are so important in affecting incidence?

Abstract 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.

Abstract A response to and comment on Pre-referral rectal artesunate in severe malaria: a flawed trial, by Karim F Hirji and Zulfiqarali G Premji.

Abstract Background Safety data regarding exposure to artemisinin-based combination therapy in pregnancy are limited. This prospective cohort study conducted in Zambia evaluated the safety of artemether-lumefantrine (AL) in pregnant women with malaria. Methods Pregnant women attending antenatal clinics were assigned to groups based on the drug used to treat their most recent malaria episode (AL vs. sulphadoxine-pyrimethamine, SP). Safety was assessed using standard and pregnancy-specific parameters. Post-delivery follow-up was six weeks for mothers and 12 months for live births. Primary outcome was perinatal mortality (stillbirth or neonatal death within seven days after birth). Results Data from 1,001 pregnant women (AL n = 495; SP n = 506) and 933 newborns (AL n = 466; SP n = 467) showed: perinatal mortality (AL 4.2%; SP 5.0%), comprised of early neonatal mortality (each group 2.3%), stillbirths (AL 1.9%; SP 2.7%); preterm deliveries (AL 14.1%; SP 17.4% of foetuses); and gestational age-adjusted low birth weight (AL 9.0%; SP 7.7%). Infant birth defect incidence was 1.8% AL and 1.6% SP, excluding umbilical hernia. Abortions prior to antenatal care could not be determined: abortion occurred in 4.5% of women treated with AL during their first trimester; none were reported in the 133 women exposed to SP and/or quinine during their first trimester. Overall development (including neurological assessment) was similar in both groups. Conclusions These data suggest that exposure to AL in pregnancy, including first trimester, is not associated with particular safety risks in terms of perinatal mortality, malformations, or developmental impairment. However, more data are required on AL use during the first trimester.

Abstract Background Malaria kills. A single rectal dose of artesunate before referral can reduce mortality and prevent permanent disability. However, the success of this intervention depends on caretakers' adherence to referral advice for follow-up care. This paper explores the dilemma facing caretakers when they are in the process of deciding whether or not to transit their child to a health facility after pre-referral treatment with rectal artesunate. Methods Four focus group discussions were held in each of three purposively selected villages in Mtwara rural district of Tanzania. Data were analysed manually using latent qualitative content analysis. Results The theme "Caretakers dilemma in deciding whether or not to adhere with referral advice after pre-referral treatment with rectal artesunate" depicts the challenge they face. Caretakers' understanding of the rationale for going to hospital after treatment - when and why they should adhere - influenced adherence. Caretakers, whose children did not improve, usually adhered to referral advice. If a child had noticeably improved with pre-referral treatment however, caretakers weighed whether they should proceed to the facility, balancing the child's improved condition against other competing priorities, difficulties in reaching the health facilities, and the perceived quality of care at the health facility. Some misinterpretation were found regarding the urgency and rationale for adherence among some caretakers of children who improved which were attributed to be possibly due to their prior understanding. Conclusion Some caretakers did not adhere when their children improved and some who adhered did so without understanding why they should proceed to the facility. Successful implementation of the rectal artesunate strategy depends upon effective communication regarding referral to clinic.

Abstract Background Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria. Methods Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success. Results Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether. Conclusion Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy.

Abstract Introduction This paper reviews recent trends in the production, supply and price of the active ingredients as well as finished ACT products. Production and cost data provided in this paper are based on an ongoing project (Artepal). Stability data are derived from a development project on rectal artesunate. Discussion The artemisinin raw material and its derivatives appear to be very stable compared to the finished products. Supply of artemisinin changed in May 2004 when the Global Fund shifted financial support to qualified countries from chloroquine or sulphadoxine-pyrimethamine to an ACT for treatment of malaria. First, there was a sudden shortage of the starting material, and short term scarcity led to a steep rise in API price: it increased dramatically in 2004, from $350 per kg to more than $1000. Second, there was a parallel increase in the number of companies extracting artemisinin from 10 to 80 between 2003 and 2005 in China, and from 3 to 20 in Vietnam. Commercial cultivation began also in East Africa and Madagascar. A steady and predictable demand for the crop can eliminate such wide fluctuations and indirectly contribute to price stability of the herb, the API and ACT. With appropriate mechanisms to reduce those fluctuations, the cost of artemisinin might decrease sustainably to US$ 250–300 per kg. Conclusion Today the global health community is facing the risk of another cyclical swing with lower demand feeding into reduced planting of A. annua and, thereafter, a new shortage of the raw material and higher API prices. International donors, the largest purchasers for ACTs could better coordinate their activities, in order to guarantee purchase of ACTs and consequently of API with manufacturers. In parallel, the base of quality producers of APIs and finished ACT products needs to be broadened. While the ACT programme is still in its early stages, the consequences of another wave of artemisinin and ACT shortages would permanently discredit it and impede any progress in rolling malaria back.