Embryotoxicity of the artemisinin antimalarials and potential consequences for use in women in the first trimester

Abstract

Single oral doses of artesunate, dihydroartemisinin, arteether and artemether administered to rats during a sensitive period of organogenesis caused embryo deaths and malformations (malformed long bones and ventricular septal defects). Extended oral dosing (12 days or more) of monkeys once daily with 12 mg/kg-d artesunate also caused embryo deaths. The initial embryotoxic effect in both species was to kill primitive erythroblasts which are present in the embryo for a few days of gestation in rats and several weeks in primates. The malformations that occurred in rats are attributed to a transient depletion of the primitive erythroblasts. In monkeys, when treatment at 12 mg/kg-d was shortened to 3 or 7 days, the embryos survived but likely suffered a transient loss of primitive erythroblasts. Limited clinical data including 123 first trimester pregnancies have not indicated any adverse effects on pregnancy. However, in rats and monkeys, the embryonic erythroblasts are much more sensitive to artemisinins than are erythroblasts in the adult bone marrow; the latter are indicated by decreases in reticulocyte count. Since decreases in reticulocyte count occur at therapeutic doses in humans, there is reason for concern that any treatment of pregnant women during the putative sensitive period (from approximately postconception Day 21 to approximately postconception week 9) that causes even minor decreases in adult reticulocyte count could also cause a marked depletion of embryonic erythroblasts which could lead to death or malformation of the embryo.