The safety of artemisinins during pregnancy: a pressing question

Every year over 50 million pregnancies occur in areas where malaria is endemic, mostly in sub-Saharan Africa. Malaria can have serious consequences for the mother and her baby. In regions where malaria transmission is unstable, pregnant women are at high risk of developing severe malaria, spontaneous abortion, stillbirth or premature delivery[1]. In high transmission regions, infected pregnant women are often asymptomatic but parasitaemia can cause maternal anaemia and low birth weight (LBW), a leading cause of infant morbidity and mortality. About 8–14% of LBWs and 3–8% of infant mortality in sub-Saharan Africa are attributable to pregnancy-associated malaria (PAM)[2].

The WHO recommends a three-pronged approach to control of malaria during pregnancy which includes effective case management, intermittent preventive treatment (IPT) and insecticide-treated nets (ITN). Until recently, WHO recommendations for case management during any trimester of pregnancy were chloroquine (CQ), or sulphadoxine-pyrimethamine (SP) in CQ-resistant areas and, alternatively, quinine in areas where neither were effective. There is limited information on the safety profile of most antimalarials used for treatment or prevention of malaria in pregnancy. In a period of increasing parasite resistance to inexpensive, conventional antimalarials such as chloroquine, SP and quinine, there is a pressing need to identify drugs which have the most favourable harm-benefit balance for these vulnerable patients [3, 4]. Artemisinins are a potentially valuable alternative as they are highly effective, act rapidly and are well-tolerated. In addition, they have the potential to reduce the transmission of malaria and to slow development of resistance[5]. In 2002, after a detailed review of published and unpublished data, a WHO expert committee concluded that artemisinins could be used during the second or third trimesters if no suitable alternative was available[6] However, treatment in the first trimester was not recommended unless the life of the woman was at risk because of concerns raised by animal experiments which suggested that artemisinins might be teratogenic and cause foetal resorption. Further studies have confirmed the embryotoxic effects of artemisinin and its derivatives in animals, including primates, with risk being confined to a defined period of gestation [7, 8]. However it remains unknown how these findings translate to man. Because of these safety 'signals' from animal models, there is an urgent need to establish the safety profile of this class of drugs in pregnancy. By June 2006, 37 countries in Africa had adopted ACTs as the first or second line treatment policy [9] and consequently pregnant women are likely to be increasingly exposed to ACTs; many women will be exposed in the first trimester before they are aware of their pregnancy. This review examines all published and ongoing studies reporting exposure to artemisinins during pregnancy and discusses their safety during pregnancy.

Electronic searches were made using MEDLINE/PubMed, EMBASE (1980 – July 2006) databases and through the Cochrane Central Register of Controlled Trials (CENTRAL). Reference lists from identified articles and conference abstracts, including those of the Multilateral Initiative on Malaria (MIM) conference, 2005, and the American Society of Tropical Medicine and Hygiene (ASTMH) annual meeting, 2005, were reviewed. The National Institute of Health's list of clinical trials was searched.

The internal and external validity of each study was assessed based on reporting comprehensiveness, the representativness of the study population, how bias and confounding factors were accounted for, and the power of the study.

Maternal adverse events and pregnancy outcomes in the artemisinin group and comparison groups (where applicable) are summarized in Tables 2 and 3 respectively.

None of the studies included in this review revealed an increased risk of serious maternal adverse effects, adverse birth outcomes, or neuro-development deficits associated with the use of an artemisinin drug during pregnancy. However, these studies were not designed to assess safety endpoints and, although they were sufficiently powered to answer the original study objective, the studies were under-powered to detect rare safety outcomes, or small differences in adverse event rates, between the comparison groups.

The very low prevalence of congenital anomalies reported can partly be explained by the complex nature of birth defect ascertainment; ideally a dysmorphologist should have assessed all newborns for abnormalities that would not be detected by an untrained physician. It was also not possible to assess the expected rate of adverse birth outcomes in any of the study settings due to the lack of background population data on rates for abortions, stillbirths and congenital abnormalities. Four studies which looked for neurological damage following artemisinin exposure revealed no indication of neurotoxicity. However, in the light of recent debates about the potential ototoxicity of the artemisinins, further studies conducting thorough auditory evaluation before and after treatment may be needed [29‐31].

The studies reviewed were highly heterogeneous in terms of treatment used, outcomes assessment, population and follow up rate. Different artemisinin drug regimens were used with varying control treatments as a comparator and six studies did not have a control group but compared the rates of adverse birth outcome to community rates derived from separate studies. Most of the studies used an artemisinin derivative combined with another drug, which adds to the difficulty of teasing out individual drug effects and restricts comparison between studies. Four studies used artesunate in combination with mefloquine; use of the latter in pregnancy has caused concern because of an increased risk of stillbirth in women who received this drug during pregnancy in one study [32] although this was not found in others. [33‐36]. The methods used to monitor adverse event and birth outcomes also differed widely between the studies. Under-estimates of adverse outcomes cannot be ruled out, particularly for early pregnancy loss in the mass drug administration campaign in the Gambia. There are no statistics on expected rate of early pregnancy loss, and determining the prevalence of spontaneous abortion is difficult. In western countries, miscarriages occur in 10 to15% of pregnancies, mostly during the first few weeks. The prevalence of miscarriages is likely to be even higher in resource poor setting. When assessing maternal AEs, there is the methodological challenge of differentiating between the effect of malaria and its treatment which is difficult to do. Furthermore, the severity of malaria episode varied between the different study populations since three included women who had already experienced a treatment failure whilst nine others included some asymptomatic women. Furthermore, the study in the Gambia was preventive; as the majority of the participants in this study are unlikely to have had malaria, lower rates of adverse birth outcomes would be expected compared to those of studies of malaria case management. The allocation of interventions could have been influenced by many factors particularly for the non-randomized studies, such as prognostic factors (severity or malaria attack rates, parasite resistance, mother's age, gravidity, other drugs etc.), which could themselves influence birth outcome and treatment response. There is, therefore, a potential for selection and detection bias. Maternal malaria has been associated with stillbirth, abortion and LBW and these adverse end-points are also considered as possible indicators of an adverse event related to drug administration[1]. Furthermore, none of these studies controlled for other drug use, which could potentially influence pregnancy outcomes.

Most of the information on artemisinin exposure during pregnancy comes from studies conducted in Southeast Asia, at the antenatal clinics of the Shoklo Malaria Research Unit among women of the Karen ethnic minority. The RCTs had robust design and randomly allocated treatment groups, although the investigators were not blinded to the treatment group. Follow up of infants varied between these three studies (49 to 80%) and only 46 infants were followed up to one year of age and examined for developmental abnormalities in the non-comparative studies. The women enrolled in these studies are likely to be representative of this population group (Karen ethnic minority) as over 90% of the women in the studied Thai-Burmese border region attend ANCs. These findings cannot be extrapolated directly to sub-Saharan Africa considering geographic differences in parasite species, resistance pattern, transmission intensity and host immunity.

A number of studies of artemisinin treatment in pregnancy are in progress (Table 4), which will contribute further to knowledge on the safety of these drugs. However, except for the phase IV study being conducted by the Centres for Disease Control in Tanzania, these studies focus on 2^nd and 3^rd trimester pregnancies. The results of animal studies suggest that if there is a safety issue related to the administration of artemisinins in pregnancy this is likely to occur very early in pregnancy. Only 123 documented first trimester exposures have been reported and this does not provide enough evidence to determine safety. Moreover, an "all or nothing rule" seems to apply for exposure during the first weeks of pregnancy. Animal experiments suggest that congenital abnormalities occur only after exposure over a narrow dose range and over a limited period of time and that exposure usually lead to a normal pregnancy outcome or death of the foetus. Developmental toxicity studies in the monkey confirmed findings from rodent studies; with embryo death induced at therapeutic dose ranges [37]. The teratogenic effect is thought to involve red blood cells production, erythropoiesis, which implies the human sensitive period would be within the first trimester of pregnancy [38]. An effect of ACTs on early pregnancy loss will be difficult to detect, especially in communities where artemisinins are likely to be used most frequently. More extensive studies are needed that will be able to detect rarer outcomes and any congenital abnormalities that might result from exposure in the first trimester of pregnancy. Ethical constraints will prohibit randomized trials of artemisinins in the first trimester of pregnancy in most communities where alternatives exist until more information on safety has been obtained. Thus, data will largely have to come from observational studies.

Unfortunately, most countries in sub-Saharan Africa do not have the infrastructure and resources for routine pharmacovigilance and very few have a formal system for routine collection of data on possible drug related adverse effects [39]. In industrialized countries, a variety of post-marketing surveillance techniques is used. Case reports and case series are the first source of information to detect adverse events in pregnancy. Although these are useful in the generation of hypotheses of a possible safety signal, specific pharmaco-epidemiological studies using a cohort or case-control approach are required to evaluate teratogenic risk. The main factors impeding the implementation of pharmacovigilance in poor countries include limited access to healthcare facilities, availability of most prescription drugs from the informal market, poor labelling of medicines, counterfeit and sub-standard pharmaceutical products, a high level of illiteracy, poor record keeping and a shortage of qualified healthcare professionals. Special pharmaco-epidemiological studies will be needed to assess the safety profile of a product's use outside the controlled environment of clinical trials. Active surveillance systems could use the existing sentinel demographic surveillance sites (DSS), which already undertake regular household visits to obtain more information on drug usage and adverse effects during pregnancy. However, these studies are expensive and not sustainable in the long term and should be restricted to newer products or following identification of new safety concerns for an older drug. Antenatal clinics (ANC) could make a useful platform for routine surveillance, as a high proportion of pregnant women attend an ANC at least once during pregnancy in sub-Saharan Africa [40]. It is necessary to develop a more pragmatic pharmacovigilance system that can be linked to a routine health information system and ideally a mix of different approaches should be used to assess the safety profile of individual drugs for pregnant patients.

Malaria in pregnancy is a major public health issue and infected pregnant women need prompt treatment with effective drugs. Although artemisinin derivatives and combinations have an excellent efficacy profile, there is very limited data on the safety of artemisinin use during pregnancy particularly in sub-Saharan Africa. Although a few studies of the safety and efficacy of artemisinins during pregnancy are currently underway, these will not produce data on the safety of artemisinins during the first trimester of pregnancy. Post-marketing pharmacovigilance of artemisinin use during pregnancy is needed urgently as ACT is implemented in almost all countries in Africa. Innovative pharmacovigilance tools, methods and systems are needed to monitor the safety of artemisinins and other antimalarials.