How do we know if medicines are safe during pregnancies?
Expectant mothers have long been excluded from clinical trials. Some experts say this practice needs to change.
Jyoti Madhusoodanan is a science writer based in Portland, Oregon. This story originally featured on Undark.
Since the start of the COVID-19 pandemic, scientists have churned out research papers at an unprecedented rate. Among the most closely watched studies are clinical trials, which are designed to determine whether a given treatment is safe and effective in humans. Hundreds of these trials have been approved around the world over the past six months. And yet one group of patients—pregnant and lactating mothers—are being left out.
An analysis of 927 COVID-19 clinical trials across Asia, Europe, and North America published online in May found more than half explicitly excluded pregnant women. Others simply failed to mention that pregnant women could enroll. Only 16 trials—less than 2 percent—were pregnancy-specific, meaning they aimed to evaluate a treatment’s effects on fetuses and expectant mothers. This means that even as researchers learn which treatments work for most people, there will be a gap in the medical community’s understanding of how these treatments perform during pregnancy.
The problem is not unique to studies of COVID-19. For decades, expectant mothers have been considered a vulnerable group to be shielded from potential harms of research for the sake of their fetuses’ health. This view stems, in part, from tragedies caused by two now-infamous drugs that were widely prescribed to pregnant women in the mid-20th century: thalidomide, which caused thousands of children around the world to be born with flipper-like limbs and other birth defects, and diethylstilbestrol (DES), which was linked to higher rates of cancer in both mothers and the daughters born to them.
But some experts say that regulations aiming to prevent such disasters could cause damage of a different kind. The near absence of clinical trial data leaves pregnant women “widely exposed” to drugs that have not been vetted for use in pregnancy, says bioethicist and OB/GYN Anne Lyerly of the University of North Carolina. Excluding pregnant women from clinical trials doesn’t eliminate risk, she points out. It simply shifts the risk from research studies to the doctor’s office, where pregnant women receive treatments rarely supported by robust data about how they will respond and whether the drugs are effective in pregnancy.
In fact, today, little is known about how the vast majority of drugs affect maternal and fetal health. One study, published in the journal Obstetrics and Gynecology in 2002, found that 90 percent of the drugs approved by the U.S. Food and Drug Administration from 1980 to 2000 had an “undetermined” potential to cause fetal malformations. “Inadequate information is available for pregnant women and their physicians” to decide whether the benefits exceed the risks for most drugs introduced during the study period, the authors concluded.
Over the past few years, federal agencies have made changes that, in principle, should help to include more pregnant women in clinical trials. But closing the data gap, some say, will also require a shift in how risk is conceptualized. Currently, when it comes to research, “the focus is so often on fetal risk that we’ve failed to recognize the benefits of including pregnant women,” says bioethicist and OB/GYN Amina White, also at the University of North Carolina.
Pregnant women should have access to drugs that have been vetted for safety, says White. “It’s an issue of justice.”
Today’s clinical research is guided by a set of principles laid out in 1979 by a federal commission that had been created five years before with the aim of bolstering the ethical underpinnings of research conducted on humans. Key tenets outlined in the final report included beneficence, the notion that researchers have an obligation to maximize benefits and minimize risks, and justice, which ensures that the benefits and burdens of research are equitably distributed to all populations.
Fears about whether administering drugs during pregnancy violates these principles can be traced back to problems with drugs developed decades earlier. Launched in 1938, DES was marketed as a preventive for miscarriages and premature births. The drug was widely used, despite a 1953 study finding no effect on either outcome. In 1971, researchers found the drug caused a rare vaginal cancer in girls born to those who took DES while pregnant, leading to an FDA warning against its use in pregnancy. Subsequent research revealed additional risks to pregnant women who had been prescribed the drug and their daughters.
Beginning in 1957, another drug, thalidomide, was distributed to thousands of pregnant women around the world as a remedy for morning sickness. (Notably, the FDA did not approve the drug for sale in the US at the time due to lack of evidence for its safety.) In the 1960s, reports began to emerge of severe birth defects in babies born to women who had taken the drug; researchers and regulators eventually recognized it as the cause of limb malformations in babies and stopped its use in pregnancy. “Those events clearly had a bearing on recommendations that ended up being codified in the federal regulations we have today,” White says.
Thalidomide’s unusual risks were partly a result of unfortunate timing—the symptoms of morning sickness typically coincide with the time when limbs are forming in the womb. Generally, drugs taken early in pregnancy have greater odds of affecting the formation of organs and other body parts, while drugs taken later in a pregnancy may affect brain development and birth weight. “The concern that you may disrupt something in these early stages”—with potentially lifelong consequences—“carries a huge weight,” says pediatrics researcher Christina Chambers of the University of California, San Diego.
In 1977, the FDA issued guidelines that excluded pregnant women and women “with childbearing potential” from phase I and phase II clinical trials, where new drugs are tested for their safety and efficacy. Inclusion in some studies became possible with the passage of the NIH Revitalization Act of 1993, which sought to increase gender and racial diversity in clinical trials.
But while pregnant women are now able to enroll in studies, concerns about their participation linger. Federal regulations currently require any study involving pregnant women to meet 10 criteria, including that, “where scientifically appropriate,” data first be collected on pregnant animals and non-pregnant human subjects to assess risk, and that any risk to mother or fetus be “the least possible for achieving the objectives of the research.”
Whether these protections would catch another thalidomide-like drug before tragedy occurs is unclear. “I would hope it would be detected,” says OB/GYN Beatrice Chen, vice chair of the Institutional Review Board at the University of Pittsburgh. Chen notes, however, that sometimes a drug’s risk to mother and fetus isn’t discovered until after it comes to market.
This is why some researchers say regulators have taken the wrong lessons from the thalidomide tragedy. “It wasn’t that research was done and it was harmful,” says Lyerly. “The problem,” she says, is that thalidomide “was distributed for widespread use” without first testing it for safety.
Recent regulatory changes have been made to include more pregnant women in studies. One crucial shift is classifying pregnant people as “medically complex” rather than “vulnerable.” The latter is a term usually reserved for prisoners and other groups at risk of exploitation or unable to make decisions for themselves, says bioethicist Maggie Little of Georgetown University. In 2018, the U.S. Department of Health and Human Services removed pregnant women from its list of subjects “vulnerable to coercion or undue influence.” Draft guidance from the FDA published in 2018 avoids the term entirely in recognition of the need to include pregnant women in clinical research.
“The change that’s now needed is a cultural shift,” Little says. “Instead of thinking it’s unethical to do research with pregnant women,” researchers should consider that “it’s unethical not to include them.”
But federal regulations don’t mandate inclusion. The final call rests with the specialists on institutional review boards, who still tend to err on the side of caution, says University of Pennsylvania OB/GYN Michal Elovitz. For example, when Elovitz and her colleagues launched a trial for convalescent plasma to treat COVID-19, they were asked to submit extensive support for their decision to include pregnant and lactating mothers. Plasma transfusions are commonly used to help with pregnancy-related problems, such as certain immune disorders or bleeding, so the reams of evidence they had to provide to allow pregnant women to participate felt “a bit excessive,” Elovitz says. In such instances, regulators need to reconsider what evidence of safety they consider sufficient for a trial to be conducted, she adds. “We have to be careful about where benevolence crosses over to patriarchy.”
Trials that include pregnant women are often costlier, and they take longer to launch, given the additional safety and monitoring requirements. To glean evidence of whether a drug is safe and effective in pregnancy, researchers also need to enroll sufficient numbers of pregnant mothers, which can increase the size of a trial. In addition, drug makers worry about insurance for liability if harm occurs, Lyerly says.
With little incentive for inclusion, most drugs on the market today are approved without any data on their use in human pregnancy. As a result, that data is still usually obtained after the drugs reach market, where women’s experiences and possible side effects are tracked over time in registries. But this design creates biases, experts say, since women are only likely to report severe reactions that they perceive as being related to their use of a drug while pregnant. Milder reactions such as headaches or fatigue may go unnoticed and registries rarely, if ever, keep score of instances where neither mother nor offspring experienced negative side effects. “That limits the generalizability of any ‘evidence’ that appears to come from registries,” White says.
There is growing acknowledgement that drugs are not the only risk to fetuses—maternal disease is, too. If left untreated, for example, diabetes increases the risk of congenital abnormalities from 3 percent to as high as 25 percent. Untreated hypertension can cause babies to be born several weeks premature. But until recently, researchers didn’t have enough data to know which existing medications could most effectively minimize these risks and whether drugs that were being prescribed carried risks of their own.
To identify solutions, the NIH began to fund studies of how drugs were metabolized in pregnancy. Simply observing metabolic changes in blood samples yielded new information, such as finding that quicker kidney filtration during pregnancy meant that pregnant women needed higher doses of drugs that were filtered out of the blood by the kidneys. This was true of both a common diabetes drug and a new HIV drug.
Surveys suggest that many pregnant women are keen to participate in clinical research. In 2013, researchers tested a common hypertension drug to treat pre-eclampsia, a life-threatening pregnancy complication. Although already coping with high-risk pregnancies, study participants said they enrolled because they preferred assuming the risk of any potential side effects to access the drug’s benefits to delivering a baby at 34 weeks—the likely outcome of leaving their condition untreated.
In other cases, patients find themselves unable to access treatments they need outside of trials. Thirty-seven-year-old Marisa Sprowles was born with hepatitis C, the fallout of a blood transfusion her mother had after knee surgery as a child that had then been passed on to her. The viral infection is curable, although treatments have historically been expensive and only covered by insurance for patients with advanced symptoms. Newly pregnant, Sprowles jumped at the opportunity to access treatment via a small clinical trial at Magee-Womens Research Institute in Pittsburgh. Her own infection was cured, and her and her husband’s now 2-year-old son was born disease-free.
“There’s been a slight movement of the needle,” says Sylvia LaCourse, an infectious disease researcher at the University of Washington in Seattle. One large UK-based study of COVID-19 drugs, the Recovery trial, does include pregnant and lactating women. And in response to feedback, the World Health Organization amended the COVID-19 clinical trial it’s sponsoring to permit the inclusion of pregnant women. “Whenever there’s a successful large-scale trial that includes pregnant women, it sets a precedent,” says LaCourse. Even a small number of pregnant study participants, she adds, can illuminate whether a drug might behave differently during pregnancy.
Of course, greater inclusion doesn’t eliminate risk. But in a closely monitored study, it does make it possible that potentially harmful drugs can be caught before they affect thousands in unfathomable ways. Clinical research minimizes the potential for harm, Lyerly says. “There’s no way to take the risk away entirely. But if you don’t look, it doesn’t mean it goes away.”