Credit: Susan Elden, DFID
The research, published today in The Lancet Infectious Diseases is the fruit of joint project between investigators from around the world to conduct the largest individual patient data meta-analysis to date under the WWARN umbrella. The study found that artemether-lumefantrine (AL) and other artemisinin-based combination therapies (ACTs) were significantly more effective than quinine, the current recommended treatment. Authors urgently call for further investigation into dose optimisation for pregnant women to ensure the highest possible treatment success.
Pregnant women are particularly susceptible to malaria, with the infection adversely affecting both mother and fetus. An estimated 60% of pregnant women in the world live in malaria endemic regions, with 125 million pregnant women at risk every year. Despite this, expectant mothers have been hugely understudied in antimalarial clinical trials. Typically, this group was excluded from clinical trials due to concerns over drug safety on the fetus, however the last two decades have seen increasing evidence that commonly used malaria treatments are in fact safe. Despite this, there are no agreed guidelines to assess antimalarial drug efficacy during pregnancy.
At present, quinine with clindamycin is the recommended drug to treat women during their first trimester of pregnancy. However, clindamycin is not widely available in malaria-endemic areas and quinine monotherapy is commonly used throughout all trimesters.
In this study, WWARN conducted an individual patient data meta-analysis of existing data from 4,968 pregnant women from 19 studies across 10 countries – representing 92% of patients in the available literature. Pooling and standardising the data from many regions and time-periods into a single dataset for analyses increases the statistical power needed to address key knowledge gaps, particularly when the existing data is sparse. Researchers assessed the efficacy and tolerability of quinine-based treatments and ACTs, including AL, the most commonly used ACT.
Authors found that the efficacy and tolerability of ACTs was better than that for quinine. AL had the best tolerability, but the lowest efficacy in comparison to other ACTs. Authors suggest the lower efficacy may be because dosing of AL is too low and recommend further investigation into dose optimisation.
First author on the study Dr Makoto Saito says: “As the safety of ACTs have been shown previously, the most efficacious drug with fewer side effects should be used to minimise the adverse impact of malaria on mother and fetus. Although the current dosing of ACT for pregnant women may not be optimal, pregnant women no longer have to put up with quinine.”
“We found that women in their first pregnancy or with higher malaria parasite burden were at a higher risk of treatment failure and should be carefully monitored”
In high malaria transmission areas, there was recurrence of falciparum malaria in 58.0% of women within 28 days of quinine treatment, while there was 13.8% recurrence after AL treatment. In low transmission areas, both treatments were more efficacious but 33.6% of women treated with quinine had recurrence within 28 days. Regardless of transmission intensity, over 95% of women treated with all other ACTs were free of recurrence.
Presence of gametocytes, the sexual precursor cells of malaria parasites were more frequent after quinine treatment compared with ACTs, this favours the use ACTs as they will be reducing the overall transmission of malaria parasites. Quinine was associated with lower tolerability due to higher risks of side effects such as abdominal pain, nausea and vomiting. This could be further exacerbated by morning sickness in the first trimester, the time during which quinine is recommended. As pregnant women infected with malaria generally have less symptoms than non-pregnant women, they are less likely to tolerate adverse drug events.
Authors caution that updated variable local patterns of resistant to antimalarial treatments should be considered when applying these findings to specific settings, and also both efficacy and tolerability of ACTs need to be re-assessed if a new dosing regimen is proposed for pregnant women.
Prof Philippe Guérin, Director of WWARN and senior author on the study says: “The findings of this study as well as evidence of safety shown in previous research provides compelling evidence that quinine provides lower efficacy and tolerability than ACTs. Further research into drug dosing to ensure optimum treatment effectiveness for both mother and fetus is paramount.”
Read the research: Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis. The Lancet Infectious Diseases.
Notes to editors
The WorldWide Antimalarial Research Network (WWARN)’s mission is to generate innovative tools and reliable evidence to inform the malaria community on the factors affecting the efficacy of antimalarial medicines. WWARN works with collaborators to optimise the efficacy of antimalarial medicines and treatment regimens, especially for vulnerable groups including pregnant women, infants and malnourished children, and provides evidence to inform the development of new antimalarial drugs.
At the request of health communities working on specific infectious diseases, the WWARN model has now been expanded beyond malaria and in 2016 the Infectious Diseases Data Observatory (IDDO) began developing data platforms for emerging and poverty-related infectious diseases. IDDO is actively working on the response to COVID-19 pandemic.
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Dellicour S, Sevene E, McGready R, et al. First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies. PLoS Med 2017; 14(5): e1002290.