Before a vaccine ever reaches your arm, it faces a rigorous testing and approval process. Vaccine studies include thousands of people representing the age groups, underlying health conditions, and geographies most affected by a given disease. Research is overseen by ethics committees, institutional review boards, and data safety monitoring agencies. Regulatory reviews are just as arduous; experts in everything from chemistry and pharmacology to manufacturing and labeling examine vaccine applications. It’s a long road that ensures patients know the benefits and any potential risks before getting a vaccine.
Unless they’re pregnant, that is.
Pregnancy can make people more vulnerable to disease, and more likely to experience severe outcomes if they fall ill. Yet, pregnant and breastfeeding people are routinely left out of initial clinical trials of new and improved vaccines.
Their omission is understandable: there are increased risks during pregnancy that make researchers and parents alike cautious. Plus, not all clinical studies are appropriate for pregnant people.
For example, Phase 1 studies demonstrate basic vaccine safety. These studies need as few variables as possible across participants to produce clear data.
But often, pregnant people are also excluded from the later stage trials necessary to license a vaccine—which means regulators and policymakers must leave pregnancy out of a vaccine’s approval or recommendations for use.
“Without specific guidelines, health care workers have little basis on which to provide advice to patients,” says Jessica Fleming, PhD, PATH Maternal Immunization Delivery Lead. “Pregnant people are left to choose between forgoing potentially lifesaving vaccines or receiving them without fully understanding the potential benefits and/or risks to themselves and their babies.”
A legacy of omission
This isn’t a new issue: even long-used vaccines have weak or even conflicting guidance for pregnant people. Regulators (like the US Food and Drug Administration) can only use clinical trial or safety surveillance data to make judgments about who should receive a vaccine; however, policymakers (like the US Centers for Disease Control and Prevention) weigh disease risk and data from a broader range of studies when making vaccine recommendations.
Influenza vaccine is a prime example: the package insert states there are no adequate and well-controlled studies in pregnant women, and that vaccines should be used only if clearly needed. Yet, health care providers fully recommend the vaccine for pregnant patients given their heightened vulnerability to the virus and the vaccine’s real-world performance.
A similar situation played out with COVID-19 vaccines. Since they became available, experts have seen no biological reason why they would pose any risk during pregnancy. But, without clinical studies including pregnant people, there is limited data to support this assumption—and vaccine guidance must clearly state the need for more evidence when making their recommendations.
“We should celebrate COVID-19 vaccines and push researchers to study them—and all appropriate vaccines—in pregnant people as soon as they can.”— Niranjan Bhat, MD, Senior Medical Officer, PATH
A shift in the status quo
The reasons to exclude pregnant people from clinical trials can range from the biological to the legal. Vaccines may function differently in pregnancy due to physiological changes in the body. Researchers must consider possible risks to the fetus as well as to the expectant parent. And researchers and developers are wary of liability in the case of adverse outcomes, whether or not they’re associated with the vaccine.
Medical research has often struggled with how and whether to include pregnant people, and even women at all. After clinical studies of the drug thalidomide in pregnant women in the 1950s and 1960s led to devastating birth defects, the US FDA issued a policy discouraging the inclusion of women of childbearing age in research. In practice, though, this led to all women being excluded. The policy was changed in 1989, but it wasn’t until 1993 that a law mandating the inclusion of women and minorities in government-funded research was passed.
These practices have had profound impacts that continue to this day, including a lack of clarity around how disease presentation, drugs, and therapies operate in male versus female bodies; a hesitancy to prescribe medications as readily to women as to men; and an erosion of trust between health care workers and some patients.
“We’ve made a lot of progress,” says Niranjan Bhat, MD, PATH Senior Medical Officer. “Women now account for nearly half of all participants in National Institutes of Health–funded trials that include both women and men. But the legacy of excluding pregnant people continues to loom large in vaccine research, detracting from this overall achievement.”
That sentiment is becoming more widespread. Pregnant people have wrestled with questions about vaccination for years, but the COVID-19 pandemic has put the issue into sharper relief.
Concerned parents, scientists, and public health experts alike are speaking out about the need for better information for pregnant people as soon as possible. Vaccine manufacturers are now adding pregnancy trials to their development strategies at an earlier stage. As a result, clinical studies of COVID-19 vaccines in pregnant participants are already underway, and observational studies and safety monitoring systems are gathering data that can help better inform a decision.
“Successful COVID-19 vaccines are being developed at speeds we’ve never seen before,” says Dr. Bhat. “We should celebrate these vaccines and push researchers to study them—and all appropriate vaccines—in pregnant people as soon as they can.”
Advancing information equity
The question of how to include pregnant people in clinical trials is highly complex.
For instance, manufacturers need to confirm vaccine safety with as few variables as possible, and pregnancy has many. Studying vaccines first in healthy, non-pregnant people reduces the chance of seeing a lot of background health events (such as heart attacks and strokes or miscarriage, stillbirth, and birth defects) that might have nothing to do with the vaccination itself. Pregnant people may also be less interested in participating in a clinical study than the general population, so it could be a challenge to enroll enough volunteers for sufficient data. And there are ethical considerations around conducting research that affects two people (a parent and their baby) with one vaccination.
But including pregnant people in studies shouldn’t be avoided for difficulty, and it shouldn’t be an afterthought. Pregnant people are a medically complex population about whom more data are needed, not less.
It’s important the changes we’re seeing don’t end with COVID-19 vaccines. In the future, we should continue to push vaccine developers to include pregnant people in clinical studies as soon as it is safe to do so. Avoiding any delays will increase information equity, vaccine access, and help overlooked populations make better decisions about their health.
“The pandemic has shifted multiple paradigms for vaccine development,” says Dr. Bhat. “We must ensure that rapid inclusion of pregnant people is one of them.”