Teratogen update: Malaria in pregnancy and the use of antimalarial drugs in the first trimester.

Malaria is a particular problem in pregnancy because of enhanced sensitivity, the possibility of placental malaria, and adverse effects on pregnancy outcome. Artemisinin-containing combination therapies (ACTs) are the most effective antimalarials known. WHO recommends 7-day quinine therapy for uncomplicated Plasmodium falciparum malaria in the first trimester despite the superior tolerability and efficacy of 3-day ACT regimens because artemisinins caused embryolethality and/or cardiovascular malformations at relatively low doses in rats, rabbits, and monkeys. The developmental toxicity of artesunate, artemether, and DHA were similar in rats but artesunate was embryotoxic at lower doses in rabbits (5 mg/kg/day) than artemether (no effect level = 25 mg/kg/day). In clinical studies in Africa, treatment with artemether-lumefantrine in the first trimester was observed to be highly efficacious and the miscarriage rate (≤3.1%) was similar to no antimalarial treatment (2.6%). When data from the first-trimester use of largely artesunate-based therapies in Thailand were pooled together, there was no difference in miscarriage rate compared to quinine. However, individually, artesunate-mefloquine was associated with a higher miscarriage rate (15/71 = 21%) compared to other artemisinin-based therapies including 7-day artesunate + clindamycin (2/50 = 4%) and quinine (92/842 = 11%). Thus, appropriate statistical comparisons of individual ACT groups are needed prior to assuming that they all have the same risk for developmental toxicity. Current limitations in the assessment of the safety of ACTs in the first trimester are a lack of exposures early in gestation (gestational weeks 6-7), limited postnatal evaluation for cardiovascular malformations, and the pooling of all ACTs for the assessment of risk.