Even when research poses minimal risk of harm to the fetus, pregnancy often results in exclusion from research — sometimes, without clear justification. “As an obstetrician-gynecologist, I have seen how the reluctance to include pregnant participants in research has resulted in profound gaps in our knowledge of the safety, efficacy, and proper dosing of drugs for use in pregnancy and lactation,” says Amina White, MD, MA, clinical associate professor in the department of obstetrics & gynecology at the University of North Carolina at Chapel Hill. “These evidence gaps have been especially problematic in HIV research on new antiretroviral therapies, from which pregnant individuals are often excluded.”

To learn more about decisions regarding whether to include pregnant participants, White and colleagues surveyed 93 IRB members and 39 IRB administrators.1 The study stemmed from a larger project, Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES), the authors of which developed concrete guidance for responsibly including pregnant participants in HIV research.2 “We conducted this survey of IRB members to better understand what they would consider minimal-risk research, and their willingness to approve such research with pregnant participants even outside of the HIV research context,” White explains.

Even when IRB members deemed a study to be minimal risk and determined the inclusion of pregnant participants would be ethically and legally permissible under current federal regulations, many remained reluctant to approve enrollment. Some IRB members cited uncertainty on whether inclusion of pregnant participants could affect the study’s scientific validity. Others acknowledged they were relying on the common, default practice of excluding pregnant individuals without requiring justification for their exclusion. “Guidance is needed to assist researchers and IRB members in characterizing the risk level of research procedures in the context of pregnancy,” White suggests.

IRBs should require researchers to provide clear and compelling justification for excluding pregnant individuals from enrollment (or continuation in a trial, if pregnancy occurs after enrollment). “We need to continue to shift the paradigm from a presumption of excluding pregnant individuals to one of responsibly including them in clinical research, especially minimal risk research,” White says.

Pamela Payne, D.Bioethics, MSN, NP, says COVID-19 vaccine research brought the issue of including pregnant research participants to the forefront. “Initially, pregnant women were excluded from trials, but organizations like ACOG pushed to have them included, which did happen,” says Payne, an instructor at the Patricia A. Chin School of Nursing at Cal State Los Angeles.

Payne says there is a pressing need to know about the safety or efficacy of medications taken during pregnancy. “What happens if a woman needs medication for a seizure disorder, and we are not certain if it’s safe to continue or if we need to adjust the dosages for the metabolic changes of pregnancy?” Payne asks.

Mostly, clinicians are forced to rely on anecdotal evidence, such as reports of outcomes of women taking medications before realizing they are pregnant. “With so many new medications coming out rapidly, it’s important for us to know whether they are safe during pregnancy,” Payne says.

Often, “the automatic, knee-jerk reaction of IRBs” is to exclude pregnant participants, Payne notes. By doing so, IRBs do not have to worry about adverse outcomes in this population.

The same is true for pharmaceutical companies. IRBs could ask researchers if they have considered inclusion of pregnant participants. If not, why not? “Some IRBs are beginning to ask the question more routinely, largely due to advocacy by ACOG and other professional organization,” Payne notes.

In general, IRBs tend to call in experts for consultation about medications during pregnancy. “But what they need to do is call in maternal/fetal experts routinely for IRB evaluations,” Payne asserts.

This allows experts to become more familiar with IRBs and allows IRBs to receive input on other research proposals that could safely include pregnant participants. It might require additional precautions, such as more frequent reports to the safety review board. “But there are ways of protecting women and their fetus in pregnancy while still allowing them to be part of a trial,” Payne says.

Katrina Heyrana, MD, PhD, a fellow in family planning at Los Angeles County and University of Southern California Medical Center, notes women experience physiological changes in pregnancy that could change the dose or route of administration needed to make a treatment efficacious or safe. “When pregnant people are excluded from clinical trials, we are just guessing at the safety and efficacy of the medications we give them because those variables have not been assessed in a pregnant population in a clinical trial setting,” Heyrana says.

For example, a higher dose of a drug may be needed for it to be efficacious due to changes in plasma distribution or metabolism. A higher dose may be toxic, leading to complications that could affect both mother and fetus. “We don’t know these things if we don’t study them in a controlled setting. Pregnant patients live in a limbo where we are offering them treatments based on our best guesses of their efficacy based on historical experience or clinical consensus,” Heyrana laments.

This also raises the ethical principle of justice. “We ask pregnant patients to make clinical decisions all the time based on the best evidence available, which is frequently not high-quality evidence,” Heyrana says.

This is because the continued understanding of pregnant women as a “vulnerable population,” despite the fact the FDA has removed this categorization, becomes a justification to exclude them from clinical trials.

“Pregnancy doesn’t change a person’s ability to weigh risks and benefits or their autonomy over their own bodies. They should have the opportunity to use the same kind of decision-making they’re using to navigate prenatal care and pregnancy complications to decide whether they accept the risks of entering an experimental study,” Heyrana offers.

IRBs and researchers face the same ethical imperative. “They should be looking for protocols to include pregnant people,” Heyrana says. “If they aren’t being explicitly recruited into the study, at least have a plan for their enrollment rather than blanket exclusion of this population.”

REFERENCES

  1. White A, Grady C, Little M, et al. IRB decision-making about minimal risk research with pregnant participants. Ethics Hum Res 2021;43:2-17.
  2. The PHASES Working Group. Ending the evidence gap for pregnant women around HIV & co-infections: A call to action. Executive summary. July 2020.