The Evidence Gap in Pregnancy: When Protection Becomes Exclusion

Why protecting pregnant patients from research may leave them exposed to uncertainty

Written by Aamir Wahhab

A new vaccine has been tested in tens of thousands of people. The results are compelling: it substantially reduces the risk of a potentially dangerous infection, and the evidence supporting its safety and effectiveness is robust.

But there is a catch. You’re pregnant, and the clinical trials that generated this evidence did not include people like you.

Would you still take it?This was the position Dr. Catherine Mezzacappa, an internal medicine resident physician, found herself in early 2021 when deciding whether to take the newly released COVID-19 vaccines. Writing in STAT, an American health news website, she described the experience of trying to interpret guidance that had been developed without data from pregnant participants. 

“As a pregnant woman, I was left trying to interpret vague guidelines developed without data from clinical trials about people like me,” she wrote.

Mezzacappa ultimately chose to receive the vaccine, but her experience exposed a much broader problem in clinical research. 

Pregnant people receive medications, vaccines and other medical interventions all the time, yet remain substantially excluded from the research used to guide those treatments. A 2025 World Health Organization analysis found that only 4% of clinical trials globally over the previous decade included pregnant women. In Canada, CIHR reports that only 3% of clinical trials recruited pregnant participants.

The result? Millions of pregnant women make high-stakes decisions about their health, and that of their developing fetus, with far less evidence than everyone else gets.

A history of benevolent protection

This exclusionary practice has a particularly painful history, originating from some of medicine’s most difficult lessons.

In the late 1950s, thalidomide was sold to pregnant women to treat morning sickness, resulting in thousands of babies being born with severe birth defects. Around the same time, doctors were prescribing diethylstilbestrol (DES) to prevent miscarriages. Decades later, the daughters of women who took it developed rare cancers and other serious health problems. These experiences understandably shaped a culture of caution around medication use during pregnancy.

But caution can take different forms. Rather than asking how pregnant people could be safely included in research, medicine increasingly treated pregnancy itself as a reason for exclusion. The intention was protective: if a treatment had not been proven safe during pregnancy, perhaps the safest thing was simply not to study it in pregnant people.

The problem is that benevolent protection can still have unintended consequences. When protection becomes synonymous with exclusion, pregnant patients may be left needing treatment without the evidence needed to guide those decisions.

That is the challenge at the heart of this issue. In trying to shield pregnant people from the risks of research, we may have exposed them to something worse: the inability to make informed, evidence-based decisions about their health.

The uncertainty doesn’t disappear

The problem with excluding pregnant people from research is that pregnancy does not mean they stop needing medical care. Pregnant patients still develop infections, experience chronic illnesses, require surgery, take medications and make decisions about vaccines. When evidence is missing, clinicians are often left to extrapolate from studies conducted in non-pregnant populations.

But pregnancy is not simply a matter of adding a fetus to an otherwise “normal” body. Pregnancy results in complex physiological changes that can affect how medications are absorbed, meaning that a standard dose may not work as well, or may become toxic. Evidence from non-pregnant adults therefore cannot always be assumed to translate directly to pregnancy.

COVID-19 made this problem difficult to ignore. An analysis of COVID-19 clinical trials found that 97.8% of vaccine trials and 70.7% of treatment trials excluded pregnant participants. Yet pregnant people still became infected, hospitalized and treated for COVID-19. They still had to decide whether to receive vaccines and medications.

Exclusion did not remove the risk. It simply moved the uncertainty from the research setting into the clinic.

This is where the issue becomes more than a question of study design. It becomes a question of who gets to benefit from medical knowledge. If an entire population is routinely left out of the research used to establish how treatments work, that population is left disproportionately responsible for navigating the uncertainty that follows.

Why is exclusion still the default?

If the consequences are so significant, why does exclusion persist?

Part of the answer is that there is no single barrier to remove. Researchers worry about fetal risk and how hard pregnancy is to study. Ethics boards and regulators prefer to minimize the risk of adverse effects. Drug companies may have little financial incentive to pay for expensive trials, particularly for older, off-patent drugs. And many research teams simply lack the infrastructure or expertise to run pregnancy studies.

Individually, each concern can seem reasonable. Collectively, however, they can create a system in which exclusion becomes the path of least resistance.

And this is part of what makes the problem so difficult to recognize. Exclusion does not necessarily look like discrimination. It can look like caution, administrative convenience, financial pragmatism or an attempt to minimize liability. But the cumulative effect is the same: pregnant patients are left with less evidence to guide their care.

From protection from research to protection through research

This does not mean that every clinical trial should enroll pregnant people. Some treatments may be too risky, and some research questions may genuinely require exclusion. Instead, the goal should be justified inclusion: pregnancy should not be treated as an automatic reason for exclusion.

Achieving this requires more than changing eligibility criteria. Pregnancy needs to be considered earlier in drug development, with appropriate funding and expertise to study it well. Ethics boards and regulators need frameworks that distinguish genuine scientific or ethical concerns from assumptions about pregnancy. For medications with little commercial incentive for pregnancy-specific research, public investment may also be necessary.

Most importantly, pregnant patients deserve more than protection from research. They deserve protection through research.

Medicine was right to take the risks of thalidomide and DES seriously. But the answer to those tragedies cannot be to keep pregnant patients out of research. It should be to build a better research system that gives patients and clinicians the evidence they need precisely when the stakes are highest.

References

1. World Health Organization. (2025). Equity and health: The inclusion of pregnant and breastfeeding women in clinical trials. https://www.who.int/news/item/18-06-2025-equity-and-health--the-inclusion-of-pregnant-and-breastfeeding-women-in-clinical-trials

2. Canadian Institutes of Health Research. Inclusion across the lifespan in health research. https://cihr-irsc.gc.ca/e/54784.html

3. McKiever, M., Frey, H., & Costantine, M. M. (2020). Challenges in conducting clinical research studies in pregnant women. Journal of Pharmacokinetics and Pharmacodynamics, 47(4), 287–293. https://doi.org/10.1007/s10928-020-09687-z

4. Mezzacappa, C. (2021). The effect of COVID-10 vaccines will – finally – be tested in pregnant people like me. STAT. https://www.statnews.com/2021/02/19/vaccinated-while-pregnant-studies-needed/

5. National Academies of Sciences, Engineering, and Medicine. (2024). Advancing clinical research with pregnant and lactating populations: Overcoming real and perceived liability risks. The National Academies Press. https://doi.org/10.17226/27595

6. Sewell, C. A., Sheehan, S. M., Gill, M. S., Henry, L. M., Bucci-Rechtweg, C., Gyamfi-Bannerman, C., Lyerly, A. D., McKinney, L. C., Hatfield, K. P., Baer, G. R., Sahin, L., & Nguyen, C. P. (2022). Scientific, ethical, and legal considerations for the inclusion of pregnant people in clinical trials. American Journal of Obstetrics and Gynecology, 227(6), 805–811. https://doi.org/10.1016/j.ajog.2022.07.037

7. van der Graaf, R., van der Zande, I. S. E., den Ruijter, H. M., Oudijk, M. A., van Delden, J. J. M., Oude Rengerink, K., & Groenwold, R. H. H. (2018). Fair inclusion of pregnant women in clinical trials: An integrated scientific and ethical approach. Trials, 19, 78. https://doi.org/10.1186/s13063-017-2402-9

8. Waggoner, M. R., & Lyerly, A. D. (2022). Clinical trials in pregnancy and the “shadows of thalidomide”: Revisiting the legacy of Frances Kelsey. Contemporary Clinical Trials, 119, 106806. https://doi.org/10.1016/j.cct.2022.106806

9. Kons, K. M., Wood, M. L., Peck, L. C., Hershberger, S. M., Kunselman, A. R., Stetter, C., ... & Deimling, T. A. (2022). Exclusion of reproductive-aged women in COVID-19 vaccination and clinical trials. Women's Health Issues, 32(6), 557-563. https://doi.org/10.1016/j.whi.2022.06.004