From no to yes: the history and ethics of including pregnant women in clinical trials

Abstract

How often have you seen or heard ‘do not take this medication if you are pregnant (or nursing)’? Whether in media advertisements, pharmacies or provider offices, pregnant women are often warned to avoid many things. However, often the evidence behind these recommendations is not clearcut. The reason is that for a long time, pregnant women were excluded from participating in clinical trials. The ethical framework that led to telling women ‘no’ to participating in clinical trials continues to make it difficult to recruit women into research studies. However, the importance of including pregnant women and instead saying ‘yes’ is critical for the future of pregnancy therapeutics. The last few decades have seen major changes in the landscape of research ethics. Very few areas have seen changes the scope of those seen regarding the inclusion of pregnant women in clinical trials, particularly medication trials. In the wake of many revelations of unethical research, including problems arising from research involving drugs in pregnant women, children and the fetus, a protectionist research ethics model was adopted. Codified by the National Research Act in 1974, reproductive-aged women were excluded from many trials to avoid accidental early fetal exposure. Vulnerable populations such as pregnant women were given additional protections, such that unless there was a compelling reason for inclusion, pregnant women would not be included in research. The general proscription model, however, was unsustainable as both clinicians and researchers realized that clinical trial data was not always generalizable from studied populations (usually men) to pregnant women. Pregnancy introduces an array of physiological changes that render dosing models from many clinical trials irrelevant. Owing to these changes, drug concentrations in pregnant women may be too low to be effective [1–3]. However, there was great concern about including pregnant women in clinical trials due to the often unknown effects drugs may have on the developing fetus. The lack of long-term developmental safety information for almost any drug further compounded this concern. In addition, animal model data had given false reassurance in the high-profile case of thalidomide. During the late 1980s, however, a growing debate occurred about including pregnant women in clinical trials. Two landmark clinical trials helped push the ethical discussion forward and away from the strict protectionist model. The international studies demonstrating that prenatal vitamin supplementation (with folic acid) could reduce the incidence of recurrent and primary neural tube defects represented a departure from prior clinical trials that were centered on treating a condition [4,5]. These studies were about giving drugs (even if only prenatal “As the inclusion of pregnant women in clinical trials has moved from ‘no’ to ‘yes’, ethical models and the informed consent process are guiding forces leading to medical answers and breakthroughs that improve the lives of pregnant women and their babies.”