Which malaria treatment is right for first trimester pregnancy?
A WHO-commissioned WWARN meta-analysis helped change what treatments the World Health Organization (WHO) recommends for treating malaria in the first trimester of pregnancy. Instead of analysing just the published results, as in a standard meta-analysis, the WWARN meta-analysis pooled and analysed data from individual participants in many studies. This analysis allowed researchers to demonstrate that artemisinin-based combination therapies (ACTs) did not increase congenital abnormalities, miscarriages or stillbirths, as was feared, while being were just as effective as the much older treatment previously recommended by the WHO.
Following WWARN’s report, the WHO switched to recommending artemether-lumefantrine (AL) for first trimester pregnancy malaria treatment. AL is the most commonly used artemisinin combination therapy on the market.
Artemisinin-based combination therapies (ACTs) have been in use since the late 1990s, transforming the treatment of malaria as they are far more effective. However, up until late 2022, the WHO still recommended the 200-year-old drug quinine rather than ACTs for one particular group of patients: women in their first three months of pregnancy.
This was because animal studies have suggested that artemisinin could potentially be toxic to the developing embryo, and in the absence of clear evidence for this vulnerable group of patients, policy makers tend to be cautious. At the same time, pregnant women are often excluded from many clinical studies, so clear evidence for antimalarial drugs’ effectiveness and safety is scarce, even though this is a group that is particularly vulnerable to the ill-effects of malaria.
So the WWARN team took a different approach: small numbers of pregnant women have been included on occasion in previous studies, and many women living in malaria-endemic areas were already being accidently exposed to ACT treatment in early pregnancy.
This is because quinine is often just not available to patients in large parts of malaria endemic areas, and sometimes women early in pregnancy may not be aware of their pregnancy status, and therefore have been treated by ACTs.
By clubbing together individual participant data from these patients from many different studies around the world, WWARN researchers were able to build up a cohort large enough to provide more robust clinical evidence, which would be impossible to do in in any one individual study.
For this study WWARN scientists worked with colleagues in Burkina Faso, Thailand, Tanzania, Rwanda, Kenya, the USA and the UK to assemble data from over 34,000 pregnancies from 10 countries in sub-Saharan Africa and Southeast Asia.
This data assemblage, combining data collected over more than 20 years, makes this the largest study of its kind.
An analysis of this data found that first-trimester artemisinin-based treatment was just as safe, and possibly more effective, than the quinine-based treatment : compared to treatment with quinine, first-trimester pregnant women treated with artemether-lumefantrine (the most commonly used ACT globally) were 42% less likely to suffer from adverse outcomes such as pregnancy loss or congenital malformations.
Following the publication of these results, the WHO changed its recommendation for treating uncomplicated malaria in women in the first three months of pregnancy, recommending treating with ACTs (preferably artemether-lumefantrine), rather than quinine.
“These results illustrate the power of sharing, harmonising and reusing data – it is unlikely that any single study would not have been able to find such a clear result, which health policy makers need to make properly-evidenced recommendations” says study author and WWARN Director Philippe Guerin.
“The results also highlight just how precious this data is - it took over 20 years to collect these data, showing just how difficult it can be collect good quality data for vulnerable populations living in low-resource settings.”
“It is imperative that such data should not be single use.”
Dr Makoto Saito, the study’s first author, said “This change also means that clinics, often in low resource settings, no longer have to stock an additional drug, quinine, just for women in their first trimester of pregnancy – all patients can be treated with the same drug, simplifying treatment and making service delivery easier.
All of the data aggregated for this study is available to any non-profit researcher across the world, via the WWARN data inventories.
Since 2022, WHO began recommending ACTs for all stages of pregnancy. This policy change is likely to have affected roughly 4 million pregnant women in sub-Saharan Africa infected with falciparum malaria in the first trimester, and has potentially averted roughly 0.12 million fetal deaths.
Read more about the WWARN meta-analysis.