A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy

Abstract

Malaria during pregnancy, particularly Plasmodium falciparum malaria, has been linked to increased morbidity and mortality, which must be reduced by both preventive measures and effective case management. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) to treat uncomplicated falciparum malaria during the second and third trimesters of pregnancy, and quinine plus clindamycin during the first trimester. However, the national policies of many African countries currently recommend quinine throughout pregnancy. Therefore, the aim of this article is to provide a summary of the available data on the safety and efficacy of artemether-lumefantrine (AL) in pregnancy. An English-language search identified 16 publications from 1989 to October 2011 with reports of artemether or AL exposure in pregnancy, including randomized clinical trials, observational studies and systematic reviews. Overall, there were 1,103 reports of AL use in pregnant women: 890 second/third trimester exposures; 212 first trimester exposures; and one case where the trimester of exposure was not reported. In the second and third trimesters, AL was not associated with increased adverse pregnancy outcomes as compared with quinine or sulphadoxine-pyrimethamine, showed improved tolerability relative to quinine, and its efficacy was non-inferior to quinine. There is evidence to suggest that the pharmacokinetics of anti-malarial drugs may change in pregnancy, although the impact on efficacy and safety needs to be studied further, especially since the majority of studies report high cure rates and adequate tolerability. As there are fewer reports of AL safety in the first trimester, additional data are required to assess the potential to use AL in the first trimester. Though the available safety and efficacy data support the use of AL in the second and third trimesters, there is still a need for further information. These findings reinforce the WHO recommendation to treat uncomplicated falciparum malaria with quinine plus clindamycin in early pregnancy and ACT in later pregnancy.

Figure 1

Flow diagram showing the number of records retrieved, screened and included in this review article. Records were identified by searching publication and clinical trial databases. Duplicates were removed and the remaining records were screened based on their titles, abstracts or clinical trial information. Based on this screen, records judged not to feature any data on the subject of artemether or AL safety, efficacy or pharmacokinetics in human pregnancy were excluded. Of 57 full text articles assessed for eligibility, 39 articles were excluded as they did not include specific reports of artemether or AL exposures during pregnancy and two articles were excluded to avoid duplication of pregnancy exposures. Sixteen relevant articles were therefore identified and included in this review article *1948–2011; **English-language articles. All years; ^†All years; ICTRP, International Clinical Trials Registry Platform.