Assessment of the safety of artemisinin compounds in pregnancy

It was considered important for WHO to evaluate the outcomes of pregnancies where early exposures to the artemisinin compounds have occurred so that any risks can be properly evaluated. The regulatory position on the minimum number of early pregnancies necessary to increase confidence about safety was that if there is information showing no increase in overall congenital malformation rates in at least 300 first trimester pregnancies treated with artemisinins then this would demonstrate a less than 10 fold increase in overall malformation risk. Information on absence of increased malformations in 1000 pregnancies would demonstrate a less than a 2 fold increase in malformation risk (EMEA, 2006). Therefore, further studies to try to achieve these numbers of first trimester pregnancy exposures is necessary. Current pregnancy warning labels were discussed. In the context of malaria endemic countries, such warnings might be of limited value if drugs are commonly used without medical supervision. Antimalarial medicines may be used during the early stages of pregnancy without the woman being aware she is pregnant. Studies in animals are very valuable in indicating possible risks from drugs. Preclinical studies in rodents have demonstrated that artemisinins can induce fetal death at high dose levels but that at lower doses congenital malformations may be produced. The malformations can only be induced in rodents within a narrow window in early embyogenesis. Evidence was presented that the mechanism by which embryotoxicity was produced was through a toxic action on the very earliest developing red blood cells to cause severe anaemia in the embryo. If this was sufficiently severe the embryos died, but in surviving embryos malformations were induced. Limited data in primates presented for the first time at this meeting suggested that artemisinins may have a similar mechanism of action in the monkey leading to anemia and embryolethality. No malformations were observed in the primate studies but the studies were limited in scope. In the rat the sensitive early red cells are produced synchronously over a very limited time period so that a single exposure to the drug can result in a high proportion of cell deaths. In contrast, in the primates, a longer period of treatment of 12 days was required to induce embryonic death. In humans only limited information is available about this stage of red cell development but it is also known to take place over a longer time period and it may well be that a limited period of treatment of 2-3 days as used in malaria would not produce such serious toxic effects. As a follow up to the Pre-clinical meeting in 2006 the Clinical meeting reviewed new data from Thailand on 1530 first trimester exposures to a range of antimalarial drugs including 170 treated with artemisinins. Irrespective of antimalarial medicine used, the higher the number of episodes of P falciparum and the greater the number of times the women had to be treated in the first trimester, the greater was the chance of abortion. In addition, fever, hyperparasitaemia, older maternal age and gestational age were significant positive risk factors for an abortion in first trimester whereas drug treatments were not significantly related. Preliminary data yet to be published from other clinical work in progress - Zambia & Bangladesh- were presented. The meeting worked out the broad content of what might be achieved in the next 2 years. It mainly focussed on the potential for establishment of Antimalarial Pregnancy Registries and in addition it also discussed the nature of clinical research that might yield information on risk-benefit of treatment. Elements of the successful collaborative ARV Pregnancy Registry - a collaboration between the FDA, pharmaceutical industry and interested parties was discussed. The meeting discussed the registry model that could be applied to artemisinins in a similar collaborative effort. Pharmaceutical companies indicated that they would very much like to be part of such a collaboration - especially if WHO were involved. The Global Fund for Aids TB and Malaria (GFATM) indicated their support to such a registry, in principle. It was concluded that at present there is not yet sufficient evidence to warrant a change in the current WHO policy recommendations on the use of the artemisinin based products for the treatment of malaria in pregnancy. The current WHO Guidelines (WHO Guidelines for Treatment of Malaria, 2006) recommend that in uncomplicated malaria, artemisinin based combination treatment should be used in the 2nd and 3rd trimester, but should only be used in the first trimester if it is the only effective treatment available. In severe malaria, the artemisinins are preferred over quinine in the 2nd and 3rd trimester because of the hypoglycaemia associated with quinine. However, in the 1st trimester until more evidence becomes available on the risk benefit ratio of artemisinins, both artesunate and quinine may be considered as options. Treatment should be started without delay and whichever drug is immediately available should be used.