Pregnancy exposure registries for assessing antimalarial drug safety in pregnancy in malaria-endemic countries

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.

Figure 1. Probability that an Embryo Will Encounter Artemisinins Inadvertently During the Critical Six-Week Period of Its Development (Week Four to Week Ten), According to the Average Number of ACT Treatments Received Per Year

In the figure, χ = number of treatments per year, t = embryo-sensitive period in days (set as 42 days or six weeks), and p = period of treatment and persistence of drug (set as three days because ACTs are normally deployed as a three-day regimen and artemisinins are eliminated within hours after each dose). The inadvertently exposed group will consist of women taking ACTs for confirmed malaria and for presumed malaria. It has been estimated that over 70% of malaria episodes in rural Africa and about 50% in urban areas are self-treated without consulting trained professionals [39]. Thus, many of these will be presumptive treatments without involvement of the formal health services, diagnostic confirmation of malaria, or screening for potential pregnancy. Even if more women seek treatment at health facilities with the deployment of more expensive ACTs and rapid diagnostic tests, antimalarials are often administered disregarding any diagnostic test. Studies in Africa indicated that between 30% and 50% of patients with a negative diagnostic test (microscopy or rapid diagnostic test) were still prescribed antimalarial drugs [40,41]. These proportions are likely to increase further when successful malaria control reduces malaria exposure. (Adapted from [16].)

Figure 2. Sample Size Calculation for Pregnancy Exposure Registry by Defect Frequency and Detectable Difference

Exposed to comparison group ratio = 1:1, power = 80%, and one-sided a = 0.05. Based on the formula for cohort design described in Strom's Pharmacoepidemiology [25]: N = 1/[p(1 - R)]² × [Z_1-a√((1 + 1/k)U(1 − U)) + Z_1-ß√(pR(1 - Rp) + (P(1 - P))/k)] ² where p is the incidence of disease in unexposed; R is the minimum relative risk to detect; k is the ratio of unexposed controls to exposed, and U = (Kp + pR)/(k + 1).