Safety of treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy

There have been recent calls for the use of artemisinin-based combination therapies (ACTs) for uncomplicated malaria in the first trimester of pregnancy. Nevertheless, the 2021 WHO Guidelines for Malaria reaffirmed their position that there is not adequate clinical safety data on artemisinins to support that usage. The WHO's position is consistent with several issues with the existing clinical data. First, first trimester safety results from multiple ACTs were lumped in a meta-analysis which does not demonstrate that each of the included ACTs is equally safe. Second, safety results from all periods of the first trimester were lumped in the meta-analysis which does not demonstrate the same level of safety for all subperiods, particularly gestational Weeks 6-8 which is likely to be the most sensitive period. Third, even if there is evidence of a lack of an effect on miscarriage rate for a particular ACT, it does not follow then there are no developmental effects for any ACT. In monkeys, artesunate caused marked embryonal anemia leading to embryo death but the long-term consequences of lower levels of embryonal anemia are not known. Fourth, there have been advances in the sensitivity and usage of rapid diagnostic tests that will lead to diagnoses of malaria earlier in gestation which is less well studied and more likely sensitive to artemisinins. Any clinical studies of the safety of ACTs in the first trimester need to evaluate the results of treatment with individual ACTs during different 1- to 2-week periods of the first trimester.