Title:Ethics: Pregnancy and Research Under the Microscope

New guidance offered on Zika and the responsible inclusion of pregnant women in scientific research.

When many of us think of pregnancy, we envision a time of eager anticipation. But for hundreds of thousands of women in the United States—and millions more globally— the experience of pregnancy is complicated by serious medical illness. Heart disease, diabetes, autoimmune disorders such as lupus, and even cancer are part of the story of pregnancy for many women; malaria, HIV/AIDS, and tuberculosis impact pregnant women around the world. Left untreated, all have devastating effects on the woman’s health—and the health of the baby she will bear.

But treating disease during pregnancy also carries risk. How do medications behave in the pregnant body? Surprisingly little evidence has been gathered about the effect different drugs might have on the fetus, or on what dose of needed medication would be effective given the drastically changing physiology during pregnancy. This leaves pregnant women, their partners, and their providers facing what can be agonizing guesswork about how to treat their illnesses.

Maggie Little, PhD, a bioethicist at Georgetown and director of the Kennedy Institute of Ethics, has a mission to change that. Together with colleagues at two other universities, she is developing ethics guidance to ensure that pregnant women’s needs are represented in the global research agenda. Little and colleagues are also working to outline novel pathways that will help encourage responsible research with pregnant women.

Leading a cultural shift

For more than a decade, Little has focused on finding pathways to improve the evidence base for medication use in pregnant women. With Anne Lyerly, MD, an obstetricianbioethicist at the Center for Bioethics at the University of North Carolina at Chapel Hill, and Ruth Faden, PhD, a public healthbioethicist at Johns Hopkins’ Berman Institute of Bioethics, Little has worked to highlight the problematic exclusion of pregnant women from the broader research agenda.

“Pregnant women get ill, and ill women get pregnant,” Little says. “They, and the children they will bear, need and deserve an evidence base to make sure their needs are met.”

In 2009, Little, Faden, and Lyerly founded The Second Wave Initiative, which helped steer a cultural shift from exclusion to inclusion of pregnant women in clinical research. The initiative held its first national workshop on Georgetown’s campus, funded by the university’s Reflective Engagement grant program.

The Second Wave Initiative asserts that pregnant women should not be categorically excluded from clinical research; instead, pregnant women can and should be included in carefully designed trials that are responsive to the special scientific and ethical complexities this population presents. The initiative, which was highlighted in a special conference hosted by the Office of Women’s Health at the National Institutes of Health in 2010, spearheaded the movement to responsibly include pregnant women in clinical research.

Since the Second Wave Initiative began, an increasing number of leading health organizations have endorsed the critical need for expanded research with pregnant women, including the World Health Organization, the American College of Obstetricians and Gynecologists, and the Council for International Organizations of Medical Sciences.

Zika research without pregnant women?

The Zika virus epidemic has reminded the global health community of just how high the stakes can be when disease intersects with pregnancy. ZIKV, as the virus is known, causes devastating neurological impairments to some babies whose mothers are infected during pregnancy. The severity of Zika virus infection has galvanized the global research community to develop vaccines against the pathogen, ranging from killed, inactivated vaccines to novel DNA vaccines. However, researchers have been reluctant to include pregnant women in clinical trials for these vaccines. In fact, the majority of clinical research excludes pregnant women, even when pregnant women are critically affected by the disease being studied.

“Zika virus is of particular concern to our work because, while the virus has quite mild effects on adults, the consequences of infection for pregnant women and their fetuses can be catastrophic,” Little says. “Though the substantial burden of Zika virus lies, clearly, with pregnant women, the vaccine development community has been reluctant to include them in the research.”

In June, Little and her colleagues published ethics guidance on pregnant women and Zika virus research through a £1.2 million grant from the London-based Wellcome Trust awarded to the Berman Institute for Bioethics. Designed with input from a 15-person working group of global experts in immunology, health policy, and research ethics, the guidance offers concrete recommendations for funders, researchers, regulatory authorities, ethics committees, and other key actors to promote the equitable inclusion of pregnant women—those most affected by the Zika virus epidemic—in the Zika virus research response.

The guidance centers on three moral imperatives:

• Develop a Zika virus vaccine that can be responsibly and effectively used during pregnancy
• Collect data that are specific to safety and the ability of a vaccine to effect an immune response in pregnant women to all Zika virus vaccines to which pregnant women may be exposed
• Ensure pregnant women have fair access to participate in vaccine trials that offer a reasonably favorable ratio of research-related risks to potential benefits.

“These guidelines are essential not only to ensuring that pregnant women’s needs are met in the Zika virus response, but also for laying the foundation to ensure that we are ready to include pregnant women in the response for the next epidemic,” says Little.

HIV research and pregnancy

Little also serves as co-investigator on the Pregnancy and HIV/AIDS: Seeking Ethical Study (PHASES) project, a multi-year grant awarded to the Center for Bioethics at UNC. The project seeks to identify barriers to conducting HIVrelated research with pregnant women. Looking for novel and creative trial designs, PHASES researchers hope to discover critically needed information on treatments and preventives in pregnant women while maintaining the highest standards of safety.

Pregnant women have been prioritized within the HIV research agenda for some time, serving as a vanguard for the inclusion of pregnant women in clinical research. However, this research, which focused primarily on preventing HIV transmission to the child, often ignored the women’s own health needs, says Little. She and colleagues on the PHASES project want to ensure that pregnant women’s health needs are prioritized in future research.

As a critical component of their work to develop these ethics guidelines, the PHASES team has conducted extensive qualitative research with pregnant women in both the United States and Malawi to elicit their views of participation in research.

“This is a major advance,” says Kevin FitzGerald, SJ, PhD, of the Edmund D. Pellegrino Center for Clinical Bioethics at Georgetown University Medical Center.

“We’re starting to understand that part of the complexity of health care is how the patient or research participant sees things,” he adds. “For it to work well, health care requires that the person you’re treating be completely engaged.”

Public health, ethics, and medical innovation

The working group’s recent recommendation to include pregnant women in the Zika virus vaccine research agenda has already reached a global audience. The international research and bioethics communities have responded with support for this important goal.

“Infectious diseases impact everybody,” says Rebecca Katz, PhD, MPH, co-director of the Center for Global Health Science and Security at Georgetown. Including pregnant women in pandemic vaccine research is critical to public health emergency preparedness, she explains. “When we study disease and epidemiology, we have to include the entire population. It makes no sense to exclude populations who are impacted by a disease.”

The universities’ multiyear project through the Wellcome grant, called PREVENT (Pregnancy Research Ethics for Vaccines, Epidemics and New Technologies), is now setting sights on ethics guidance for the inclusion of pregnant women in other public health emergency research. For example, the emerging threat of Lassa fever poses particularly severe consequences for pregnant women, suggesting that their needs should be prioritized in responses to the virus.

Little is confident that Georgetown will continue to impact the world through the university’s commitments to public health, ethics for global human good, and medical innovation.

“Together with other allies at other universities, Georgetown is leading the charge to ensure that pregnant women are ethically included in the research agenda. Georgetown is uniquely positioned to contribute to this work,” Little says. “Ethics is in the DNA of Georgetown.”