Specialty grand challenge editorial innovative approaches for pharmacoepidemiologic research in pregnancy: Shifting the paradigm of Thalidomide’s impact on pregnant women

Abstract

Drug use during pregnancy is highly prevalent with 50%–81% of women reporting using at least one drug during that period (Mitchell et al., 2011; Lupattelli et al., 2014). These numbers are likely to keep increasing since women become pregnant at a later age and are more likely to have preexisting medical conditions and pregnancy complications. (Fridman et al., 2014). Even though drug use during pregnancy is commonplace, it has been estimated that nearly 98% of drugs approved by the Food and Drug Administration (FDA) between 2000 and 2010 carry an “undetermined” teratogenic risk (van Gelder et al., 2014). Furthermore, there is a dearth of information on how pregnancy-induced physiological changes impact a drug’s pharmacokinetics (Pinheiro and Stika, 2020). This uncertainty stems from the almost systematic exclusion of pregnant women from clinical trials following the thalidomide scandal. The identification in 1961 of the first human teratogenic drug, thalidomide (i.e., treatment of nausea and vomiting in pregnancy), had a profound impact on biomedical research and drug regulation (Lenz, 1988). In 1971, the banning of diethylstillbestrol (i.e., medication used to prevent miscarriages) on the US market, after being associated with cervical and vaginal cancers in female offsprings, further enhanced the fear and suspicion generated by the thalidomide tragedy (Diethylstilbestrol DES Exposure and Cancer, 2021). As a result, the FDA issued a guideline in 1977 recommending the exclusion of most women of childbearing potential from early phases of clinical trials, a policy that was widely adopted by drug sponsors (Merkatz, 1998). It took more than 10 years for the FDA to identify the perverse impact of this policy on women’s health and to issue new guidelines (FDA, 2020a). These guidelines “Guideline for the Study and Evaluation of Gender Difference in the Clinical Evaluation of Drugs” removed the restriction on the inclusion of women in early phases of clinical trials and called for more studies on the pharmacokinetic differences between genders (FDA, 2020a). Still, two decades later, clinical trials intended for pregnant women remain uncommon, with less than 0.5% of ongoing trials in 2013–2014 focusing on this group, and only 4% of those examining the pharmacokinetics of pregnancy (Scaffidi et al., 2017). Moreover, OPEN ACCESS