Because pregnant women are routinely excluded from pre-licensure clinical trials for fear of harming the mother or the developing foetus , most drugs are marketed with limited information on their safety during pregnancy and therefore are not recommended for use by pregnant women. Yet drugs are widely used by pregnant women, and medication often cannot be avoided in chronic diseases such as epilepsy and HIV or other acute illness that harm the mother and the unborn child if left untreated.
Passive mechanisms of spontaneous reporting of adverse drug effects are inadequate for detecting drug-induced foetal risks or lack of such risks . The US Food and Drug Administration and the European Medicine Agency recommend active surveillance, such as the use of pregnancy exposure registries (PERs), for products that are likely to be used during pregnancy or by women of childbearing age (WOCBAs), particularly if there have been case reports of adverse pregnancy outcome following exposure, if drugs in the same pharmacological class are known to pose risk during pregnancy, or if pre-clinical animal data suggest potential teratogenic risk [3,4]. In industrialised countries, this information can be derived from medical records and automated databases, including medical or pharmacy insurance claims. Such approaches are challenging in developing countries where resources for routine pharmacovigilance are rare and automated data sources generally do not exist [5–8]. Thus, nearly all developing countries rely on drug safety data from industrialised countries. However, there are often no or limited safety data in pregnancy for drugs targeting tropical diseases, as these are not widely used in the countries with more robust pharmacovigilance systems .
- There is an urgent need to develop targeted pharmacovigilance systems to assess the safety of antimalarials in early pregnancy.
- The artemisinins are effective antimalarials increasingly deployed in malaria-endemic countries; however, they have been shown to be embryo-toxic in animal models, and their safety in early human pregnancies remains uncertain.
- Modelling suggests that the probability an embryo will encounter artemisinins during the critical six-week period (at week four to week ten of gestation) through accidental exposure is 12% for areas where adults receive on average one treatment with three days of artemisinin-based combination therapy per year.
- Most of the approaches used in industrialised countries to evaluate a drug's embryo-foetal toxicity have limited application in resource-poor countries. Establishing an international antimalarial pregnancy exposure registry would enable a targeted prospective pharmacovigilance approach and timely assessment of the risk–benefit profile of antimalarials.
- Here we discuss methodological considerations for the systematic prospective assessment of pregnancy outcomes and congenital malformations in women exposed to antimalarials early in pregnancy, including approaches to capture drug exposure information in resource-poor settings, choice of comparison groups, and sample size considerations.
Antimalarials are a good example . Malaria can have devastating consequences for the mother and foetus [10,11], and pregnant women require prompt treatment with safe and effective antimalarial drugs when infected. The artemisinins are among the most effective and rapidly acting antimalarials to date, providing lifesaving benefits to children, adults, and pregnant women . The limited information regarding their safety is reassuring , and the World Health Organization (WHO) now recommends the use of artemisinin combination therapies (ACTs) in the second and third but not yet in the first trimester (unless alternatives are not available) , as uncertainty remains about their safety in early pregnancy (Box 1) [14–16]. ACTs are rapidly being rolled out and may soon become among the most widely used antimalarial drugs. Because there are no specific risk management precautions to exclude WOCBAs from using ACTs, the potential for inadvertent exposure to artemisinins early in pregnancy is high and in many cases unavoidable (Figure 1). Health care providers, pregnant women, and policy makers urgently need valid information to make informed decisions about the risks and benefits of ACTs for WOCBAs.
Box 1. Mechanism of Artemisinin Toxicity in Early Pregnancy
Animal reproductive toxicology studies show that artemisinin derivatives all have embryo-toxic effects at low-dose ranges in all species studied (i.e., mice, rat, rabbit, frog, and primate models) [31–34].The embryo-toxic mechanism is thought to occur through depletion of embryonic erythroblasts (primitive erythrocytes), which is associated with severe anaemia leading to cell damage and death due to hypoxia . In humans, the most sensitive time window may be between week four and week ten, when erythroblasts circulate and have not yet been fully replaced by definitive erythrocytes . In addition to the window of sensitivity, the duration of exposure is also important. Rodents have a synchronous clonal expansion of metabolically active erythroblasts, making them particularly vulnerable during a three- to four-day window early in pregnancy. In primates (and most likely also in humans), this may not be the case, as different generations of erythroblasts co-exist and are progressively replaced by definitive erythrocytes over a period of weeks . In cynomolgus monkeys, no embryo lethality or malformations were observed with three-day exposures (the typical duration of treatment with ACTs) or with seven-day exposures [31,32,35,36]. The predictive value of the animal models for humans is unclear, particularly because the duration of daily exposure is likely to be short (hours) as the artemisinins are rapidly eliminated and limited to three or at maximum seven days.
This paper describes the use of PERs as a targeted pharmacovigilance approach for assessing the safety of antimalarial drugs used during early pregnancy in resource-constrained malaria-endemic countries.