Should pregnant women be included in clinical trials?

Some say including pregnant women in medication research is too risky. A bioethicist and researcher argues that excluding them is the real danger.
Pregnant woman sits with her hand on her belly, looking at a prescription bottle her doctor holds. The doctor points out something on the prescription label.

Editor’s note: The opinions expressed by the author do not necessarily reflect the opinions of the AAMC or its members.

Each year, millions of pregnant women worldwide face a difficult decision: Should they take a medication — often for serious conditions like depression or cancer — based on slim evidence about its safety and effectiveness during pregnancy, or should they forgo the medication and risk possible danger to themselves or the child they might bear? 

In medicine we depend on good evidence to provide good care. But the research base for the use of many medications during pregnancy is so poor that some in the field have dubbed pregnant women the “last therapeutic orphans.”

It is not — as is the case with orphan diseases — that pregnant women who face illness are rare. For example, diabetes affects between 7 and 11% of pregnant women in the United States, and hypertension affects 6 to 8%, according to the Centers for Disease Control and Prevention. A 2014 Lancet review further suggests that psychiatric disorders affect well over 20% of pregnant women worldwide.

Instead, the stumbling block has been worries about testing medication during pregnancy, particularly concerns about possible risks for the developing fetus. But it’s clear that pregnant women and their babies sorely need research that addresses their particular health needs.

The research base for many medications is so poor that some in the field have dubbed pregnant women the “last therapeutic orphans.”

For one, pregnancy affects how the body metabolizes drugs, so studies in other populations do not provide much-needed data for pregnant women. What’s more, in recent decades, just 1% of studies on how drugs are metabolized provided pregnancy-specific data, according to a 2014 Frontiers in Pediatrics article.

Without these data, doctors prescribing to pregnant women can easily miss the mark between a dose that’s too low to help and one so strong it’s toxic. For instance, a 2011 study indicated that pregnancy lowers blood levels of the anti-influenza medication Tamiflu, potentially making the standard dose too weak for pregnant women. The study was conducted after the 2009 flu pandemic, during which pregnant women were significantly more likely to suffer severe morbidity or die. Getting the dose right for this at-risk population is a clear and long-overdue priority.

In addition, drug studies done with nonpregnant adults leave us in the dark regarding fetal safety. For 98% of the medications approved between 2000 and 2010, we do not know the risk to the fetus. And current postmarket surveillance will not fill the research gap — not for our patients and probably not even for our young daughters. That’s because it takes an average of 27 years after market approval for a drug to be categorized in terms of risk. 

Further, concerns about fetal safety can lead to decisions not to prescribe or take a drug, decisions that can turn out harmful — even catastrophic — for mother and fetus alike. For instance, as neurologist Myla Goldman reported at a recent Food and Drug Administration (FDA) meeting, many physicians advise women with multiple sclerosis to stop biologic therapy before becoming pregnant because of the near absence of safety data on these medications. Tragically, some women who forgo this treatment end up in a wheelchair, unable to work, or unable to care for their children or themselves. And note: It is not a concrete risk of harm, nor a careful weighing of risks and benefits, but the absence of data that led to this tragic choice and outcome.

Some say that conducting research on pregnant women is too ethically problematic. Not so. In the late 2000s, bioethicists Ruth Faden, PhD, and Maggie Little, PhD, and I cofounded the Second Wave Initiative to help ensure that the needs of pregnant women are appropriately addressed in drug and device policies. We took upending the view that ethics preclude the inclusion of pregnant women in research as our first critical task, and we crafted a manifesto of sorts explaining that ethics requires it. Pregnant women, we argued, have not benefitted fairly from the investment in biomedical research. Moreover, failing to conduct needed research with pregnant women does not eliminate risk — it just shifts it to the clinical context. That hardly describes an ethical state of affairs.

Research with pregnant women can be done and it can be done ethically. In some cases, it’s just a matter of gathering “low hanging fruit” — opportunistically but systematically collecting data from pregnant women who are already taking medications, including women who become pregnant while enrolled in a clinical trial. But more is required, including enrolling pregnant women in studies of drugs or vaccines in development that are likely to be used by pregnant women or are likely to benefit them. An important step forward would be to require studies that exclude pregnant women to justify the decision to do so.  

Research with pregnant women can be done, and it can be done ethically. In some cases, it’s just a matter of gathering “low hanging fruit” — opportunistically but systematically collecting data from pregnant women who are already taking medications.

There are some signals that the tide may be turning toward recognizing the need to include pregnant women in research. For example, the 2016 21st Century Cures Act established the Task Force on Research Specific to Pregnant Women and Lactating Women to advise the Secretary of Health and Human Services on how to close knowledge gaps around — and develop safe, effective therapies for — pregnant and lactating women. The task force is expected to report its findings later this year.  

The FDA has also signaled its support for advancing research with pregnant women. In April, the agency released draft guidance that highlights the problems of relying on postmarketing studies and provides examples of circumstances under which pregnant women could be included in research prior to marketing. (The initiative offered detailed comments, here). Importantly, the guidance calls filling current knowledge gaps, such as appropriate dosing specific to pregnancy, a “critical public health need.” 

I couldn’t agree more. The question is not whether to do research with pregnant women, but how. Our group is now working toward a better understanding of the opportunities, barriers, and ethics of inclusion. We are exploring these issues in the contexts of HIV and vaccines against emerging epidemic threats, working through the Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) funded by the National Institutes of Health (NIH) and the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) project funded by the Wellcome Trust. Our goal is to develop guidance for those in the research community who will take on the critical task of advancing the evidence base for prescribing medications during pregnancy. 

These advances are essential. It is well past time — and it is morally imperative — for research to benefit pregnant women. We need to replace tragic choices with informed, reasoned, and robustly evidence-based decisions.

Editor’s note: The PHASES Project is supported by the National Institute of Allergy and Infectious Diseases of the NIH under award number R01AI108368. The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH.

Image of column author Anne Drapkin Lyerly sitting on metal stairs outside and smiling. The image focuses on her head and upper torso.

Anne Drapkin Lyerly, MD, MA, is professor of social medicine and associate director of the Center for Bioethics at the University of North Carolina at Chapel Hill. She is cofounder of the Second Wave Initiative, an effort to ensure that the health interests of pregnant women are fairly represented in biomedical research and drug and device policies, and is principal investigator of the NIH-funded PHASES Project.