The Ethical Dilemma across history
Prioritizing protection of the fetus was an important factor that prevented pregnant women to participate in clinical drug trials. Several federal regulations now request clarification on inclusion criteria by defining whether the fetus or the pregnant woman are being targeted, and whether the study aims to highlight therapeutic or non-therapeutic outcomes [8]. In 1974, after the devastating thalidomide disaster, congress asked the newly established National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to make recommendations for the conduct of research involving pregnant women and fetuses (Federal regulations at subpart B of 45 CFR 46) [9]. Dr. Kelsey, who was the primary reviewer of the thalidomide application assigned by the FDA, delayed the approval of thalidomide over concerns of adverse effects and the drug was never approved in the United States [10]. The aim of the recommendations thus was to protect the fetus from unnecessary harm. More than twenty years later and after much deliberation, the wording was changed in 2001 to include a more proscriptive approach; stating that pregnant women or fetuses may be involved in research if all of 10 conditions are met (Table 1) . In 2002, a registry for reporting adverse effects was established. In 2004, the FDA developed the guidance on pharmacokinetic (PK) studies in pregnancy, and, in 2005, guidance was provided on clinical lactation studies and pregnancy [11]. In 2009, the Second Wave Initiative was launched aiming to systematically address the knowledge gap on treatment of pregnant women in a collaborative manner [12]. The FDA has also addressed drug labeling to include risk summary and clinical consideration in an effort to improve patient care decision and counseling under the Pregnancy and Lactation Labeling Rule (PLLR) [7]. This was first proposed in 2008 with the revised version put in action in 2014. While much has been done to support the moral imperative of including pregnant women, much more needs to be done to ensure that we provide pregnant women with beneficence, autonomy, and justice.