Ms. Cellophane: How Clinical Research Looks Right Through People with Child-Bearing Potential

Bethany T. Samuelson Bannow, MD, MCR, is an associate professor of medicine at Oregon Health & Science University in Portland.

The 2024 presidential election felt, to many of us, like a referendum on women’s health care and reproductive rights. As I write this, it’s November 6, and it would be disingenuous to say that I don’t fear for myself and, more importantly, for my daughters’ well-being. Still, I’m finding hope in the increasing interest around women’s health that I’m seeing among colleagues and the scientific community.

As a classical hematologist with a focus on hemostasis and thrombosis, the paucity of data on female-specific outcomes, such as abnormal uterine bleeding (AUB), is readily apparent. As an example, the first randomized, controlled trial of methods for managing AUB resulting from the use of factor Xa (FXa) inhibitors, which affects as many as 70% of menstruating individuals on anticoagulation,¹ was just published in 2024.² This is well over 10 years after the first FXa inhibitor entered the market. The first study that looked at using von Willebrand factor to treat AUB in patients with von Willebrand disease was also recently published in 2023.³

These strides are admirable and inspire hope, yet at the same time individuals assigned female at birth (AFAB) are still excluded from many clinical trials, whether implicitly or explicitly. The most recent example is that of gene therapy in hemophilia. Studies to date have not included AFAB individuals, and there are no known plans to study these therapies in this population in the future. While severe and moderate hemophilia are rarer in AFAB individuals than those assigned male at birth, this population is equally in need of improved therapies.

A chief concern around the inclusion of AFAB individuals in clinical trials is always the potential to become pregnant. Interestingly, a 1977 directive from the U.S. Food and Drug Administration (FDA) — the first official strike against women in clinical trials — did not distinguish between those truly at risk for pregnancy and those partnered, for example, with someone who had undergone a vasectomy. In 1993, the National Institutes of Health (NIH) somewhat reversed this policy with a new requirement that clinical trials include women and later issued requirements for consideration of sex as a biologic variable. While this policy must be applied to all NIH-funded trials, many, if not most, large clinical trials are funded by industry, not the NIH. Most such trials already require AFAB individuals to use at least two forms of reliable contraception and virtually all exclude pregnant women.

A prime example of this is the recent studies of the COVID-19 vaccine. Pregnant individuals were universally excluded from COVID-19 vaccine trials, even though they were an at-risk population with higher rates of intensive care unit admission than non-pregnant peers. This stance was taken even though the vaccine is not a live-attenuated vaccine, which is the only type that is absolutely contraindicated in pregnant individuals. Furthermore, while this effectively deemed pregnant individuals incapable of providing informed consent for a vaccine while pregnant, these same individuals were considered fully competent to provide informed consent for medical treatments and clinical studies for both themselves and their neonates from the moment the umbilical cord was cut. With this approach, it’s easy to understand why some have drawn a parallel between a pregnant person and the cellophane wrapper on a piece of candy — a disposable receptacle with the sole purpose of protecting the treasure inside.

Once the COVID-19 vaccine became available, pregnant individuals and their doctors were left with many unanswered questions. As a person who was pregnant throughout most of 2022, while there was never a question of whether I would get my booster, I spent many nights wondering and had many conversations with my obstetrician about when in pregnancy was the best time to get the booster: earlier to reduce the risk of us both being infected and in the ICU or later to extend the duration of circulating antibodies closer to my newborn’s six-month appointment, when she would be eligible for the vaccine? Ultimately, studies have shown both safety and benefit of the COVID-19 vaccine in pregnancy, and it is now recommended, but some of these questions, such as timing, remain unanswered.

So, what does all this mean for those of us in clinical practice and for our patients? In the end, we must be aware that we are often practicing with far from complete knowledge about the specific risks and benefits of therapies for this group of patients. We must also be honest with them about what we do and don’t know. While individually we have little power to convince industry-led trials to ensure inclusion of individuals at risk for female-specific conditions, such as menstruation and pregnancy in certain cases, as a collective we can continuously demand more information from the sponsors of clinical trials. We can and should report post-marketing adverse events, such as AUB, to the FDA and ask for information about these risks whenever incomplete data are presented. Perhaps if we continue to demand this information, we can bring about a change in practice that will improve our ability to care for all our patients, not just those born with the privilege of a Y-chromosome.

Bethany T. Samuelson Bannow, MD, MCR
Deputy Editor

References

1. De Crem N, Peerlinck K, Vanassche T, et al. Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists. Thrombosis Research. 2015;136(4):749-753.
2. Hamulyák EN, Wiegers HMG, Scheres LJJ, et al. Heavy menstrual bleeding on direct factor Xa inhibitors: rationale and design of the MEDEA study. Res Pract Thromb Haemost. 2021;5(1):223-230.
3. Ragni MV, Seaman CD, Gilligan D, et al. Von Willebrand disease minimize menorrhagia (VWDMin) trial. Blood. 2019;134(Supplement_1):1130.