More than a decade after the National Institutes of Health Office of Research on Women’s Health changed the classification of pregnant people from “vulnerable” to “complex,” pregnant people are still being excluded from clinical trials.
It is our role as physicians to serve all in an equity-based manner and ethically, and some require more protection from harm. But if the role of a physician is to uplift communities and/or voices of those with less privilege, equity must be applied to research endeavours. Specifically, pregnant people should be highlighted in trials rather than excluded, which perpetuates the difference in quality of care.
Historically, pregnant people were classified as a “vulnerable” population. A 2012 study indicated that 95 per cent of Phase IV clinical trials in the United States excluded pregnant individuals from their subject pool. Furthermore, 98 per cent of drugs have none or minimal data on the pharmacokinetics and/or safety data for dosing in pregnancy. A 2014 report found that only 1.3 per cent of pharmacokinetic studies were focused on pregnant individuals, very few of which were funded by industry, which has little monetary incentive to include them. In May 2020, during the height of the pandemic, only 1.9 per cent of registered clinical trials focused on COVID-19 included pregnancy. That exclusion continues to dominate the clinical trial space for acute, chronic and potentially fatal illnesses. As of January 2022, 69.4 per cent of registered clinical trials for breast cancer actively excluded pregnant people. Continuous lack of inclusion of the pregnant in clinical studies is even more concerning given that more than 80 per cent of pregnant individuals in Canada are prescribed one or more medications during pregnancy.
If pregnant people are continuously excluded from research, how can we possibly provide the same level of evidence-based medicine to them as we provide others? How can we advocate, manage and support them?
It is easy to consider the risks of including pregnant subjects in clinical research, but we equally must assess the very real but often overlooked risk of not including them, a risk that was made apparent in the 1950s when thalidomide was given to pregnant women despite their exclusion from the clinical trials, resulting in thousands of children born with severe birth defects. Statistically, this poor outcome likely would have been prevented had only 10-15 pregnant people been included in the trials. Due to differences in drug metabolism and physiology during pregnancy, inclusion in research is necessary to prevent clinical decisions based on non-generalizable data.
The historical classification of the pregnant as a “vulnerable” population was due to a few factors, including decreased ability to provide informed consent and increased susceptibility to coercion. But pregnant individuals continuously make informed health choices throughout their pregnancy and discussion early in a pregnancy of the benefits and risks of a clinical trial that occurs during labour would allow patients to make informed decisions that are not influenced by emotions, pain or situation during labour. Patients are allowed to withdraw from clinical trials at any point; if they changed their mind during labour, that decision would be respected.
Excluding pregnant people from clinical trials due to a gap in knowledge then creates an even larger gap.
Some argue that pregnant people may be at increased risk in clinical trials due to lack of scientific knowledge. However, this perpetuates a negative cycle of excluding pregnant people due to a gap in knowledge, which then creates an even larger gap. Balancing protecting pregnant people and fetuses from research while protecting women through research is a struggle. Although the potential for negative consequences for a fetus must be weighed, we must also consider a woman’s right to have autonomy over her medical options and potential direct benefits of clinical trials.
Changing the classification of pregnant people from a “vulnerable” population to a “complex” (or sometimes labelled “special”) population reflected a change in attitude. The aim was that with this change, the default assumption would be for pregnant people to be included in trials. So far, that hasn’t happened. To further spark inclusion, research approval forms should require justification for the exclusion of pregnant people.
More sophisticated statistical analysis models are needed if we hope to fill this research gap since the three per cent baseline risk of birth defects creates a barrier to the inclusion of pregnant people in trials – it can be challenging to decipher if birth defects are due to medications or are occurring in the sample due to random chance..
In the long-term, better representation in research will promote maternal and fetal well-being. From a macro-perspective, exclusion in trials leads to a much larger number of pregnant people being exposed to illness. By extension, more will be put at risk when the drug comes to market than those at risk in the trial.
Although some progress has been made, further action is needed to diminish this health disparity. In continuing to make up for lost time by using risk-benefit analysis and ethical principles to inform our choice of including pregnant people in trials (where reasonable), we are simultaneously sending a strong message that pregnant people matter in all aspects of medicine, and more specifically that they deserve the innovation, possibilities and attention research provides.