Clinical trials often exclude pregnant women, citing additional risks. However, women almost never are asked what they think about participating in those studies and the risks.

This is a mistake that some researchers are working to correct.

“Our work is part of a larger effort to make sure pregnant women’s interests are represented in research, whether it involves an emergency response or not,” says Anne Lyerly, MD, MA, professor of social medicine at the University of North Carolina (UNC) at Chapel Hill. Lyerly also is the associate director of the Center for Bioethics at UNC, and she is the principal investigator on the PHASES project, a National Institutes of Health (NIH)-funded study aimed at developing concrete ethics guidance for HIV research with pregnant women.

One part of this project is a study of how pregnant or recently pregnant women view research rules — including rules governing HIV drug clinical trials — that may exclude pregnant women.

Since the 1960s when thalidomide use in Europe led to fetal malformation — a problem the United States mostly avoided due to the FDA blocking the drug’s approval — clinical trials have been hesitant to enroll pregnant women.1

“One thing that’s been problematic is that in our ethical debates over which circumstances pregnant women should be involved in research, we have not asked pregnant women themselves about the circumstances under which they should be involved,” Lyerly says.

For a long time, the IRB community has thought that its job is to protect research participants from research risks, and fetuses are included in that protection, Lyerly notes.

“The idea is that as long as you have a strict contraception requirement and protocol, and keep exposures to risks as minimal as possible and you have the right protections in place, then you are being ethical IRB members,” she says. “We are challenging the ethical paradigm that it’s the primary responsibility of the IRB to protect pregnant women and children from research.”

This traditional view of an IRB’s role does not always protect women in the end, she adds.

For instance, pregnant women who are excluded from a clinical trial might be exposed to the same or similar medication or treatment in a non-research setting, where they would not be as closely monitored.

The long-time tendency to exclude pregnant women from research might not protect them, Lyerly adds.

“If you are unwilling to include pregnant women in the research context, then they won’t be well served in the clinical context,” Lyerly says.

Among the different ways clinical trials handle reproductive issues, one of the most common rules is to exclude pregnant women from a study and to require all other women enrolled to use one or two forms of birth control, says Kristen Sullivan, PhD, MSW, MBA, PHASES project director at the UNC Center for Bioethics in the department of social medicine.

Another way is requiring paternal consent when there is the possibility of benefit to the fetus, but not to the woman who is pregnant, Sullivan says.

“Based on U.S. regulations, the study might require paternal consent when there is only a benefit to the fetus, unless the father is unavailable or incompetent or when the pregnancy resulted from rape or incest,” she says.

Another approach entails dropping enrolled women from the study drug if they become pregnant.

“If you were in a study, the benefit in the study could be to you,” Sullivan says. “If you got pregnant, most studies would take you off the study and discontinue the study drug because of your pregnancy.”

The research team asked 140 women, including 70 from the United States and 70 from Malawi, who were HIV positive or who were at risk of being infected with HIV and who had been pregnant within the past two years, to consider the common pregnancy and study enrollment rules. Sullivan presented the study’s preliminary findings in a panel session at the PRIM&R 2017 Advancing Ethical Research Conference, held Nov. 5-8, 2017, in San Antonio.1

“We wanted to ask women who would be similar to populations that would either participate in HIV research or be likely to benefit from HIV research,” Lyerly says. “We introduced the fact that these rules were often in place and may have applied to studies, and we wanted to know what diverse women thought about these rules and policies.”

There were a divergence of views and a range of considerations that they brought to the table, Sullivan says.

More than half of the women supported the paternal consent question for a variety of reasons. Some supported paternal rights, believing the father had a shared responsibility for the well-being of the fetus, she explains.

“On the other side of the coin, many participants talked about how it was the woman who was carrying the pregnancy, and it was her body, and so it should be her choice to participate,” she says. “But what was particularly interesting was the way the women explained how important it was that the relationship dynamic be considered.”

Some women believed it was appropriate to include the father in these decisions, but only if he was invested and involved in the woman’s pregnancy, she adds.

“In Malawi, if the couple was not married, or in the U.S., if the father was not involved, many women didn’t think he should have any input into the decision,” Sullivan says. “The other piece had to do with women trying to avoid conflict and violence in the relationship, and for some women that was a reason to oppose paternal consent.”

Those women feared that some men would not allow their partners’ involvement in the study, even if the study could be beneficial.

Another challenge for clinical trial investigators is to decide how to weigh risks and benefits to the woman and fetus, and the PHASES team is working to develop an ethics framework to address that.

“There is a large and growing evidence base for treatment, using HIV medications to treat a pregnant woman to prevent disease in her newborn, and that’s standard of care,” Lyerly says. “Medications have side effects, and there are different levels of efficacy. More research is needed to optimize treatment regimens in pregnant women so they and their babies are best served.”

This can require a trade-off, and trade-offs that involve pregnancy are ethically complicated, Lyerly says.

“What we’re trying to look at, as part of our study, is how we can ensure that there is adequate evidence to make the best choices for pregnant women, in terms of their own health and in terms of preventing HIV in their children,” she explains.

The study also asks women how they feel about being required to use two forms of contraception during a clinical trial.

“For example, the requirement to take birth control was viewed by some participants as problematic,” Sullivan says. “They were concerned about the side effects of birth control, and they thought two forms were unnecessary, particularly for women who were not sexually active.”

The study’s whole point is to include women’s voices in these ethical decisions, Lyerly says.

“They can offer depth and breadth to an ethical argument that’s been around a long time,” she explains. “Some of the issues they’ve raised are morally relevant, and bioethicists and policymakers didn’t think of these because [women] weren’t asked.”

REFERENCE

1. FDA. Regulations, guidance, and reports related to women’s health. Available at: http://bit.ly/2jsZFpn.