A randomised controlled trial of three drug regimes for the treatment of malaria in pregnancy in Ghana

A thesis presented on a clinical trial of amodiaquine (AQ) and sulphadoxine-pyrimethamine (SP) used singly and in combination (AQ+SP) compared with chloroquine (CQ) for the treatment of 900 pregnant women who had falciparum malaria infection detected by a screening programme using OptiMAL antigen dipsticks during routine antenatal clinic sessions at the St. Theresa's hospital. Enrolment into the study began in March 2003 and ended in September 2004 but follow up of treated women continued to March 2005

Dihydroartemisinin-piperaquine versus artesunate-amodiaquine for treatment of malaria infection in pregnancy in Ghana: an open-label, randomized, non-inferiority trial.

To determine whether dihydroartemisinin-piperaquine (DHA-PPQ) is non-inferior to artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria infection in pregnancy. 417 second/ third trimester pregnant women with confirmed asymptomatic Plasmodium falciparum parasitaemia were randomized to receive DHA-PPQ or ASAQ over 3 days. Women were followed up on days 1, 2, 3, 7, 14, 28 and 42 after treatment start and at delivery for parasitological, haematological, birth outcomes and at 6-weeks post-partum to ascertain the health status of the babies. Parasitological efficacy (PE) by days 28 and 42 were co-primary outcomes. Analysis was per-protocol (PP) and modified intention-to-treat (ITT). Non-inferiority was declared if the two-sided 95% confidence interval for PE at the endpoints excluded 5% lower efficacy for DHA-PPQ. Secondary outcomes were assessed for superiority. In PP analysis, PE was 91.6% for DHA-PPQ and 89.3% for ASAQ by day 28 and 89.0% and 86.5% respectively by day 42. DHA-PPQ was non-inferior to ASAQ with respect to uncorrected PE {adjusted difference by day 28 (DHA-PPQ-ASAQ); 3.5% (95%CI: -1.5, 8.5) and day 42: 3.9% (95%CI: -2.7, 10.4)}. ITT analysis gave similar results. PCR to distinguish recrudescence and reinfection was unsuccessful. DHA-PPQ recipients had fewer adverse events of vomiting, dizziness and general weakness compared to ASAQ. Both drugs were well-tolerated and there was no excess of adverse birth outcomes. DHA-PPQ was non-inferior to ASAQ for treatment of malaria infection during pregnancy. No safety concerns were identified. Our findings contribute to growing evidence that DHA-PPQ is useful for control of malaria in pregnancy. This article is protected by copyright. All rights reserved

New Medicines for Tropical Diseases in Pregnancy: Catch-22

Nicholas White and colleagues discuss why it is so important to conduct clinical trials of malaria treatments in pregnancy

Prevention and management of malaria during pregnancy: findings from qualitative studies in Ghana and Malawi

BACKGROUND: In endemic regions of sub-Saharan Africa, malaria during pregnancy (MiP) is a major preventable cause of maternal and infant morbidity and mortality. Current recommended MiP prevention and control includes intermittent preventive treatment (IPTp), distribution of insecticide-treated bed nets (ITNs) and appropriate case management. This article explores the social and cultural context to the uptake of these interventions at four sites across Africa. METHODS: A comparative qualitative study was conducted at four sites in three countries: Ghana, Malawi and Kenya. Individual and group interviews were conducted with pregnant women, their relatives, opinion leaders, other community members and health providers. Observations, which focused on behaviours linked to MiP prevention and treatment, were also undertaken at health facilities and in local communities. RESULTS: ITNs were generally recognized as important for malaria prevention. However, their availability and use differed across the sites. In Malawi and Kenya, ITNs were sought-after items, but there were complaints about availability. In central Ghana, women saved ITNs until the birth of the child and they were used seasonally in northern Ghana. In Kenya and central Ghana, pregnant women did not associate IPTp with malaria, whereas, in Malawi and northern Ghana, IPTp was linked to malaria, but not always with prevention. Although IPTp adherence was common at all sites, whether delivered with directly observed treatment or not, a few women did not comply with IPTp often citing previous side effects. Although generally viewed as positive, experiences of malaria testing varied across the four sites: treatment was sometimes administered in spite of a negative diagnosis in Ghana (observed) and Malawi (reported). Despite generally following the advice of healthcare staff, particularly in Kenya, personal experience, and the availability and accessibility of medication – including anti-malarials – influenced MiP treatment. CONCLUSION: Although ITNs were valued as malaria prevention, health messages could address issues that reduce their use during pregnancy in particular contexts. The impact of previous side effects on adherence to IPTp and anti-malarial treatment regimens during pregnancy also requires attention. Overtreatment of MiP highlights the need to monitor the implementation of MiP case management guidelines

Local illness concepts and their relevance for the prevention and control of malaria during pregnancy in Ghana, Kenya and Malawi: findings from a comparative qualitative study

BACKGROUND: In sub-Saharan Africa, the burden of morbidity and mortality linked to malaria during pregnancy (MiP) is significant and compounded by its unclear symptoms and links with other health problems during pregnancy. Mindful of the biomedical and social complexity of MiP, this article explores and compares local understandings of MiP and their links with other pregnancy-related health problems. METHODS: A comparative qualitative study was undertaken at four sites in three countries: Ghana, Malawi and Kenya. Individual and group interviews were conducted with pregnant women, their relatives, opinion leaders, other community members and health providers. MiP-related behaviours were also observed at health facilities and in local communities. RESULTS: Across the four sites, local malaria concepts overlapped with biomedically defined malaria. In terms of symptoms, at-risk groups, outcomes and aetiology of malaria during pregnancy, this overlap was however both site-specific and partial. Moreover, the local malaria concepts were not monolithic and their descriptions varied amongst respondents. The symptoms of pregnancy and malaria also overlapped but, for respondents, symptom severity was the distinguishing factor. Malaria was generally, though not universally, perceived as serious for pregnant women. Miscarriage was the most widely known outcome, and links with anaemia, low birth weight and congenital malaria were mentioned. Nonetheless, amongst many potential causes of miscarriage, malaria was not recognized as the most important, but rather interacted with other pregnancy-related problems. CONCLUSIONS: Given the overlap of common pregnancy problems with the symptoms of malaria, and the limited association of malaria with its main outcomes, a comprehensive antenatal care programme is the most appropriate strategy for the provision of health education, prevention and treatment for MiP. Variations in locally shared understandings of MiP must however be taken into account when designing and promoting MiP intervention strategies

Randomized Trial of Artesunate+Amodiaquine, Sulfadoxine-Pyrimethamine+Amodiaquine, Chlorproguanal-Dapsone and SP for Malaria in Pregnancy in Tanzania

Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria.Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1ratio2ratio2ratio2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28.1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%), and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4-35) in the SP, 18/77 (23%, 95%CI 14-34) in the CD, 1/73 (1% 95%CI 7-0.001) in the SP+AQ and 7/75 (9% 95%CI 4-18) in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site.Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children.ClinicalTrials.gov NCT00146731

Assessing and Strengthening African Universities' Capacity for Doctoral Programmes

Imelda Bates and colleagues developed and validated an evidence-based tool for evaluating doctoral programmes in African universities

Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: user acceptability

<p>Abstract</p> <p>Background</p> <p>Malaria in pregnancy is associated with increased risks of maternal and foetal complications. Currently, intermittent preventive treatment (IPT) of malaria during pregnancy with sulphadoxine-pyrimethamine (SP) is recommended by the WHO as part of a package of interventions also including insecticide-treated nets and effective case management. However, with increasing resistance to SP, the effectiveness of SP-IPT has been questioned. A randomized controlled trial (RCT) to investigate the relative efficacy of an alternative strategy of intermittent screening and treatment (IST), which involves a rapid diagnostic test for malaria at scheduled ANC visits and treatment of women only if positive, versus SP-IPT has been conducted in Ashanti region, Ghana. This paper reports on a complementary study investigating the acceptability of the different strategies to women enrolled in the trial.</p> <p>Methods</p> <p>Data were collected through twelve focus group discussions with women selected at random from the different arms of the RCT, exploring their experiences and perceptions about antenatal care and their involvement in the trial. Content analysis was used to identify relevant themes to structure the results.</p> <p>Results</p> <p>Five main themes emerged from participants' experiences of ANC and the RCT that would influence their acceptability of malaria prevention strategies during pregnancy: health benefits; drugs received; tests received; other services received; and health worker attitude. Their own health and that of their baby were strong motivations for attending ANC, and reported favourably as an outcome of being in the RCT. Women were not always clear on the biomedical function of drugs or blood tests but generally accepted them due to strong trust in the health staff. Home visits by staff and free ITNs as part of the trial were appreciated. Politeness and patience of health staff was a very strong positive factor.</p> <p>Conclusions</p> <p>Overall, both intermittent screening and treatment and intermittent preventive treatment appeared equally acceptable to pregnant women as strategies for the control of malaria in pregnancy. The women were more concerned about quality of services received, in particular the polite and patient attitude of health staff, and positive health implications for themselves and their babies than about the nature of the intervention.</p

Evaluating Health Workers' Potential Resistance to New Interventions: A Role for Discrete Choice Experiments

BACKGROUND: The currently recommended approach for preventing malaria in pregnancy (MiP), intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPT), has been questioned due to the spread of resistance to SP. Whilst trials are underway to test the efficacy of future alternative approaches, it is important to start exploring the feasibility of their implementation. METHODS AND FINDINGS: This study uses a discrete choice experiment (DCE) method to assess the potential resistance of health workers to changing strategies for control of MiP. In Ashanti region in Ghana, 133 antenatal clinic health workers were presented with 16 choice sets of two alternative policy options, each consisting of a bundle of six attributes representing certain clinical guidelines for controlling MiP (type of approach and drug used), possible associated maternal and neo-natal outcomes, workload and financial incentives. The data were analysed using a random effects logit model. Overall, staff showed a preference for a curative approach with pregnant women tested for malaria parasites and treated only if positive, compared to a preventive approach (OR 1.6; p = 0.001). Increasing the incidence of low birth weight or severe anaemia by 1% would reduce the odds of preferring an approach by 18% and 10% respectively. Midwives were more resistant to potential changes to current guidelines than lower-level cadres. CONCLUSIONS: In Ashanti Region, resistance to change by antenatal clinic workers from a policy of SP-IPT to IST would generally be low, and it would disappear amongst midwives if health outcomes for the mother and baby were improved by the new strategy. DCEs are a promising approach to identifying factors that will increase the likelihood of effective implementation of new interventions immediately after their efficacy has been proven

Intermittent Screening and Treatment versus Intermittent Preventive Treatment of Malaria in Pregnancy: A Randomised Controlled Non-Inferiority Trial

BACKGROUND: The effectiveness of intermittent preventive treatment of malaria in pregnancy (IPTp) may be compromised by the spread of resistance to sulphadoxine/pyrimethamine (SP) across Africa. But little information exists on alternative drugs for IPTp or alternative strategies for the prevention of malaria in pregnancy. Therefore, we have investigated whether screening with a rapid diagnostic test and treatment of those who are positive (IST) at routine antenatal clinic attendances is as effective and as safe as SP-IPTp in pregnant women. METHODS AND FINDINGS: During antenatal clinic sessions in six health facilities in Ghana held between March 2007 and September 2007, 3333 pregnant women who satisfied inclusion criteria were randomised into three intervention arms (1) standard SP-IPTp, (2) IST and treatment with SP or (3) IST and treatment with amodiaquine+artesunate (AQ+AS). All women received a long-lasting insecticide treated net. Study women had a maximum of three scheduled follow-up visits following enrollment. Haemoglobin concentration and peripheral parasitaemia were assessed between 36 and 40 weeks of gestation. Birth weight was measured at delivery or within 72 hours for babies delivered at home. Parasite prevalence at enrollment in primigravidae and in multigravidae was 29.6% and 10.2% respectively. At 36-40 weeks of gestation the prevalence of asymptomatic parasitaemia was 12.1% in study women overall and was very similar in all treatment groups. The risk of third trimester severe anaemia or low birth weight did not differ significantly between the three treatment groups regardless of gravidity. IST with AQ+AS or SP was not inferior to SP-IPTp in reducing the risk of low birth weight (RD  =  -1.17[95%CI; -4.39-1.02] for IST-SP vs. SP-IPTp and RD = 0.78[95%CI; -2.11-3.68] for IST-AQAS vs. SP-IPTp); third trimester severe anaemia (RD = 0.29[95%CI; -0.69-1.30] for IST-SP vs. SP-IPTp and RD  =  -0.36[95%CI;-1.12-0.44] for IST-AQAS vs. SP-IPTp). CONCLUSION: The results of this study suggest that in an area of moderately high malaria transmission, IST with SP or AS+AQ may be a safe and effective strategy for the control of malaria in pregnancy. However, it is important that these encouraging findings are confirmed in other geographical areas and that the impact of IST on placental malaria is investigated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00432367 [NCT00432367]