Date Published: September 9, 2008
Publisher: Public Library of Science
Author(s): Stephanie Dellicour, Feiko O ter Kuile, Andy Stergachis
Abstract: Feiko ter Kuile and colleagues argue that there is an urgent need to develop targeted pharmacovigilance systems to assess the safety of antimalarials in early pregnancy.
Partial Text: 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.
PERs are the most common approach used to monitor drug safety in pregnancy and provide reassurance on the potential risk associated with certain drugs. They can serve both to generate hypotheses and to evaluate suspected risks or risk factors that may have been identified during pre- or post-marketing phases . In industrialised countries, 32 PERs are registered with the Food and Drug Administration . There is some variation in design, but they all use prospective approaches and identify and follow exposed women until the end of pregnancy (i.e., before the outcome is known). The systematic prospective ascertainment of pregnancy outcomes has several major advantages over case-control designs and passive surveillance. This design reduces selection bias (for example, due to self-reporting) and recall bias, has the potential to use standardised methods to assess outcome, and—because of the availability of both numerator and denominators—allows calculations of risk estimates that can then be compared against comparison groups or background population rates . One other attractive feature of PERs is that they can be time-limited and terminated once the target sample size to rule out a pre-defined risk is reached.
The design for reliably capturing the occurrence and timing of inadvertent drug exposure to ACTs in early pregnancy requires special consideration. Firstly, the critical period occurs around the time when many women may not yet be aware of their pregnancy (our current understanding from animal models of the mechanism of embryotoxicity of the artemisinins suggests that in humans the sensitive drug exposure time window is between week four to week ten of gestation [Box 1]). Secondly, retrospective determination of the precise timing of exposure is challenging since a typical treatment course is short (three days). Another difficulty is the accurate assessment of the gestational age at the time of exposure. Lastly, malaria treatment is often home-based or unsupervised and antimalarials can be obtained from a variety of providers, often over-the-counter. In contrast, antiretroviral and anti-tuberculosis drugs are typically provided by formal health services, which are more likely to keep records. Furthermore, exposures are often long-term and continuous, making it easier to determine if and when a woman was exposed to antiretroviral or anti-tuberculosis medication than with the short course of antimalarials.
The primary outcome of interest is a decisive factor for the choice of study design, study population, and target data sources for outcome ascertainment and needs to be defined a priori. Although pre-approval animal reproductive toxicology studies have ambiguous predictive value for human embryo-foetal toxicity, due to variations in species-specific effects , the current data from animal models suggest that the effects are not species-specific and that exposure early in the first trimester might cause birth defects and/or early embryo/foetal death with subsequent miscarriages or foetal resorption. Most of the existing PERs monitor all pregnancy outcomes (i.e., live births, still births, and miscarriages), but the design and sample size calculation focus on capturing birth defects . Foetal resorption and early miscarriages are very difficult to assess reliably; most will go unnoticed clinically as they occur before eight to nine weeks, with the majority occurring before three weeks . Only repeated pregnancy testing with a switch from positive to negative tests may suggest objectively early loss of pregnancy . This is unlikely to be feasible or culturally acceptable in many malaria-endemic countries, and the frequent use of pregnancy testing itself reduces the probability of inadvertent exposures in that population. We may thus have to accept that early pregnancy loss cannot be captured reliably in sufficient numbers, in contrast to later miscarriages and stillbirths.
Assessing the teratogenic potential of a drug requires comparison of the frequency of birth defects against other groups to put a signal into context. These comparison groups can be external (i.e., from peripheral sources) or internal (i.e., generated from within the same study or system).
The main determinants of sample size are the degree of the teratogenic effect to be excluded (relative risk) and the expected frequency of the endpoint of interest in the non-exposed group (Figure 2). A third factor is the type and number of potential controls. For example, with an exposed/unexposed ratio of 1:4, approximately 522 exposed women and 2,090 unexposed women are needed to exclude a 2-fold increase in major malformations detectable at birth when the predicted rate in the comparison group is 2% (power 80%, alpha 0.05). This would be 10,748/42,992 exposed/unexposed women for birth defects that occur at a frequency of one in 1,000 (such as cleft lip/palate). Such numbers will only be achievable using several sentinel sites over several years. The sample sizes will also need to account for loss to follow-up and the fact that not all births can be examined for birth defects (e.g., foetal loss with discarding of expelled foetus prior to examination by study staff). The rate of recruitment will depend on the likelihood of accidental exposure. This depends on the fertility rate and frequency of drug exposure in the population. For example, in areas where pregnancy testing is not available, the average number of ACT treatments is one per woman per year, and the total fertility rate is 5.5, the probability is only 2.5% (or one in 40 women) (Box 2; see Text S1).
Although the registry could be set up initially to address the specific question of the safety of antimalarials in pregnancy, it is essential to capture concomitant diseases and medications such as antiretrovirals because of potential drug interactions, confounding, and effect modification. As such, these additional data could contribute to PERs for other diseases such as the Antiretroviral Pregnancy Registry [26,27].
There are many methodological challenges to designing PERs for antimalarials, including those common to most pharmacovigilance methods in resource-poor countries [28,29]. The specialised nature of the reliable assessment of drug exposure and congenital malformations is not easily achievable from routine pharmacovigilance surveillance systems (where they exist). Such an effort will require dedicated sentinel sites that are capable of following WOCBAs and linking antenatal care records with treatment records, such as sites with demographic health surveillance systems or sites with captive populations where health care is provided centrally and well recorded (e.g., industrial and agricultural estates or long-term refugee camps).
The establishment of an international antimalarial pregnancy exposure registry, using specialised sentinel sites to provide reliable exposure and outcome data for the primary data collection, is a potentially cost-effective targeted approach. Central collation of the information would enable evaluation of the risk–benefit profile of antimalarials in a timely manner, and over time would allow the detection of rare adverse drug reactions that could not be detected by any single study. New levels of collaboration between pharmacovigilance programmes, antimalarial drug developers, research groups, regulatory authorities, and WHO will be essential. This international multi-product, multi-sponsor approach will require good governance structures, such as those used by the Antiretroviral Pregnancy Registry, and if successful could serve as a pathfinder for other PERs to capture much-needed safety information on other drugs used for tropical diseases .