Pregnant women with malaria in their first trimester are being excluded from clinical trials of new antimalarials, leaving doctors without safety data for the drugs they need most. This matters because malaria in early pregnancy can harm both mother and baby, yet the most effective treatments have never been properly tested in this group. The World Health Organization now recommends artemether-lumefantrine as the first-line treatment, but there is insufficient evidence on the safety of other widely used artemisinin-based combination therapies. Without this data, healthcare providers cannot offer the best options, and pregnant women face unnecessary risk. If this trial succeeds, it will generate robust evidence on the safety, tolerability, and efficacy of alternative antimalarials for first-trimester malaria. The results will feed directly into treatment guidelines and clinical practice, ensuring that healthcare providers and pregnant women have access to optimal treatment options. This could change how malaria is managed in early pregnancy across malaria-endemic regions, reducing harm to mothers and babies while supporting the WHO’s strategy of using multiple first-line therapies to slow antimalarial drug resistance.
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Background: Malaria in pregnancy can have devastating consequences, particularly in early pregnancy. Effective treatment in the first trimester can significantly improve maternal and pregnancy outcomes. However, first-trimester pregnancies are generally excluded from clinical trials resulting in new and effective antimalarials being withheld from use in early pregnancy. WHO updated its guidelines in 2022 from quinine to artemether-lumefantrine (AL) as the first-line treatment for uncomplicated malaria in the first trimester. However, there are insufficient data on the benefit-harm of other widely used artemisinin-based combination therapies. Objectives: 1) To generate robust evidence on the safety, tolerability, and efficacy of antimalarials for the treatment of uncomplicated P. falciparum malaria in the first trimester. 2) Translate research findings into treatment guidelines and clinical practice. Study design: a) Phase IIIb, non-inferiority, Bayesian adaptive randomised platform trial comparing pyronaridine-artesunate (PA) and AL in Burkina Faso, Kenya and Mali. Primary outcome: Safety. Secondary outcomes: efficacy and tolerability. b) Formative research to inform innovative trial recruitment and retention strategies, c) Acceptability and feasibility to assess values and preferences of antimalarials during early pregnancy, d) implementation research to explore factors affecting implementation of AL in the first trimester to inform translation strategies, and e) cost-effectiveness of PA vs AL. Impact: The trial will provide critical information on the safety and efficacy of alternatives to AL for treatment in the first trimester, benefiting settings where AL is not used and aligning with WHO's strategy of multiple first-line therapies against antimalarial drug resistance. Results will be translated into policy and guidelines and ultimately ensure that healthcare providers and pregnant women have access to optimal treatment options for malaria in early pregnancy.
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