Malaria is the most important human parasitic disease and is responsible of high morbidity and mortality in resource-poor countries. Pregnant women, who are a high-risk group, are almost always excluded from clinical trials; thus, the investigators lack sufficient information on the safety and efficacy of most antimalarials in pregnancy. The recommendation of the World Health Organization to use artemisinin combination therapy (ACT) in the 2nd and 3rd trimester is already implemented in several African countries, however documentation of their efficacy and safety in pregnancy is still limited. Thus, the investigators propose to evaluate the efficacy and safety of 4 ACT(artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate and dihydroartemisinin-piperaquine), when used to treat pregnant women with P. falciparum malaria; the results will help to recommend the optimal therapy for this high-risk group in Africa.

Malaria is the most important human parasitic disease. Although pregnant women are a high-risk group, they are almost systematically excluded from clinical trials, for fear of teratogenicity and embryotoxicity; thus, we generally lack sufficient information on the safety and efficacy of most antimalarials in pregnancy, as well as evidence-based recommendations for the prevention and treatment of malaria during pregnancy.

The WHO recommendation to use artemisinin combination therapy (ACT) in the 2nd and 3rd trimester is already implemented in several African countries. However, the documentation of their efficacy and safety in pregnancy is still limited, especially concerning the African contexts.

Therefore, we propose to test 4 fixed-dose combinations (artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate and dihydroartemisinin-piperaquine), to evaluate their efficacy and safety when administered to pregnant women (2nd and 3rd trimester) infected with P. falciparum. Explanatory variables will be collected for treatment failure (PCR-corrected) and for recurrent parasitaemia. The primary hypothesis tested will be the clinical equivalence (pair-wise non-inferiority) of the 4 treatment regimens with clinical equivalence defined as difference in treatment failure rates (PCR corrected) of 5% or less.

In addition, an attempt will be done to carry out in vitro testing at the time of recurrent infection. However, the success of the test will depend on the parasite density. In addition, blood samples collected on filter paper at day 0 and at day of recurrent parasitaemia will be genotyped for the search of known molecular markers related to drug resistance. Not all samples will be analyzed; rather these will be selected according to the therapeutic response so that the prevalence of molecular markers will be compared between treatment successes, true treatment failures and new infections.

Inclusion Criteria:

• Gestation of at least 16 weeks and <37 weeks;
• P. falciparum monoinfection of any density, with or without symptoms
• Hb equal or higher than 7 g/dL;
• At least 15 years old;
• Residence within the health facility catchment's area;
• Willing to deliver at the health facility;
• Willing to adhere to study requirements (including in Zambia and Malawi, HIV VCT)
• Ability to provide written informed consent; if the woman is minor of age/not emancipated, the consent must be given by a parent or legal guardian according to national law (however, in this case, the investigator is responsible to check that the woman herself is also freely willing to take part in the study, and the woman will be asked to sign for "assent").

Exclusion Criteria:

• History of allergic reactions to the study drugs;
• History of known pregnancy complications or bad obstetric history such as repeated stillbirths or eclampsia;
• History or presence of major illnesses likely to influence pregnancy outcome including diabetes mellitus, severe renal or heart disease, or active tuberculosis;
• Current cotrimoxazole prophylaxis or ARV treatment;
• Any significant illness at the time of screening that requires hospitalization, including severe malaria;
• Intent to move out of the study catchment area before delivery or deliver at relative's home out of the catchment area.
• Prior enrollment in the study or concurrent enrollment in another study.
• Unable to take oral medication
• Clear evidence of recent (1 week) treatment with antimalarials or antimicrobials with antimalarial activity (clindamycin; azythromycin; etc.)