A version of this story appeared in Science, Vol 375, Issue 6586.
Kinue Beugre learned she was pregnant one evening last July, 6 months after being diagnosed with lupus. Beugre, who is 22 years old, had already cycled through excruciating symptoms from the autoimmune disease: swelling that prevented her from flexing her fingers, itchiness that caused her whole body to shake, and joint pain that made climbing stairs impossible. Her husband brought meals to the secondfloor bedroom of their townhouse in Durham, North Carolina, where Beugre wrote poetry and pushed ahead on a master’s degree in health policy.
By the time the pregnancy test came back positive, Beugre was feeling better. A daily cocktail of drugs had tamed her body’s out-of-control inflammation. The couple was thrilled about their baby-to-be and optimistic that pregnancy would proceed smoothly. “I wasn’t so much worried about lupus,” she says.
Weeks later, Beugre’s disease flared and she faced an agonizing truth confronted by millions of people with chronic illness before her: Getting pregnant had catapulted her into a realm of unknowns. That’s because for at least 90% of prescription medications available worldwide, there’s little or no information on fetal safety because of a scarcity of human data.
The disparity comes in part because researchers, drug companies, and regulators largely exclude pregnant people from clinical trials, and there’s little incentive to investigate how babies fare after exposure to approved medications. When it comes to medical research, there’s “a sort of no-regrets policy toward pregnant people,” says Ruth Faden, a bioethicist at Johns Hopkins University, “as in, ‘Let’s not do anything, so we won’t have any regrets.’”
The problem, Faden and others say, is that without data, physicians may hesitate to recommend medications and pregnant people are often afraid to take them, sometimes with grave consequences. About 20% of pregnant people have a chronic illness, and a mother-to-be “may not survive her cancer, she may not have her diabetes well controlled, she may experience more severe postpartum depression” if her conditions go undertreated during pregnancy, Faden says. The baby can suffer, too. Flaring autoimmune diseases, for example, may trigger premature labor. On the flip side, some medicines can be harmful in pregnancy, raising the risk of congenital birth defects, developmental and other delays, or immune system problems in the baby.
Without robust evidence, “we really end up with our best-guess treatment,” says Megan Clowse, a rheumatologist at Duke University and one of Beugre’s doctors. “That’s not good enough for our patients.”
In the past few years, however, there’s been growing recognition that the status quo is unacceptable and—somehow—has to change. Regulators are urging companies to learn more about their medications in pregnancy, and doctors such as Clowse are probing drug safety for their pregnant patients in any way they can. Registries track children exposed to medications before birth, looking for concerns that may crop up later. New computer models simulate blood flow, placental biology, and fetal circulation to trace the virtual passage of chemical compounds during pregnancy. More direct approaches—adding pregnant people to clinical trials and monitoring those who get pregnant while enrolled—have been slower to get off the ground.
For people like Faden, today’s goal is modest: Narrow the evidence gap in drug safety between people who aren’t pregnant and those who are. Even that remains a challenge.
Pregnancy’s complex biology can make a drug’s impact hard to forecast. Physiological changes include a doubling of blood volume and increases in body fat and water. The placenta, through which nutrient-rich blood reaches the fetus and waste funnels out, changes to modulate the passage of substances across it. And an exposure’s timing matters. A compound that raises the risk of limb malformations, for example, is especially hazardous in early pregnancy, when arms and legs develop.
But the intricacies of biology are not the only reason for the dearth of data. Researchers, regulators, and providers want to protect a fetus, sometimes at all costs. Patients struggle with that tension as well. “If you tell a woman, ‘You’re putting your child at risk,’ of course they’re going to stop their medication. And everyone tells them that, from their mother-in-law to their nail person,” says Uma Mahadevan, a gastroenterologist at the University of California, San Francisco. Her own work has shown that inflammation from disease can be especially hazardous in pregnancy, and pregnant patients with Crohn’s disease are generally at greater risk when they discontinue therapy rather than stay on it.
History casts a dark shadow. “We don’t want another thalidomide,” Faden says, referring to the drug developed by a West German company in the 1950s. Thalidomide became popular worldwide for many conditions, including nausea in pregnancy, and reports soon surfaced of babies with missing or malformed limbs born to mothers who had taken it while pregnant. Thousands of babies were affected, many of whom died at or soon after birth. In 1961, thalidomide was pulled off the market. But its stain endured and left research on medications in pregnancy halting at best.
Regulatory hurdles also get in the way. The default has been to keep pregnant people out of many clinical trials for their own protection unless sponsors can justify including them. Drug trials that do include pregnant patients tend to focus on pregnancy-specific problems, such as preventing transmission of HIV to the fetus. When a pregnant person does enroll in a study that only the fetus stands to benefit from, U.S. regulations require obtaining informed consent from both parents. “There’s a paternalistic approach,” says Maged Costantine, a maternal fetal medicine specialist at Ohio State University, Columbus. “The old attitude has been to protect mothers from research.”
At the Food and Drug Administration (FDA), the information gap came into stark relief after a 2015 rule for prescription drug labeling to address pregnancy and lactation. As revisions of dozens of labels began, regulators discovered there was little to say. “It was a data desert,” says Lynne Yao, director of the division of pediatrics and maternal health. “It really highlighted the idea that we’ve got nothing.”
Cynthia Gyamfi-Bannerman, a maternal fetal medicine specialist at the University of California, San Diego (UCSD), has seen the damage inflicted by missing information. One of the most challenging chapters of her career came last year, at a time of medical triumph: Vaccines for COVID-19 were remarkably effective, but following standard practice, drug companies had excluded pregnant people from clinical trials. And participants who happened to get pregnant after a first vaccine dose did not receive a second. Although the companies pledged to track the outcomes of several dozen participants who became pregnant, that information wouldn’t be available for months.
As a result, Gyamfi-Bannerman says, she and other doctors who were part of a national task force crafting recommendations for pregnant people struggled without scientific data to guide them. Amid the uncertainty, she and her colleagues were besieged by patients afraid the vaccines could harm their fetus. There was limited evidence to reassure them.
The result of those fears: Only about 40% of pregnant people in the United States were fully vaccinated by the beginning of January, despite their heightened risk from COVID-19. Several studies that tracked the vaccines in pregnancy ultimately showed they were safe, and 8 months after authorization, the Centers for Disease Control and Prevention formally recommended that pregnant people get the shots. By then, dozens of unvaccinated pregnant people had died. (CDC, like many researchers, now favors gender-neutral language for those who are pregnant.)
We really end up with our best-guess treatment. That’s not good enough for our patients.
- Megan Clowse
- Duke University
A lack of data on drugs in pregnancy also poses the opposite risk: that pregnant people will take a drug that proves harmful. New Zealander Denise Astill has epilepsy, and her twin daughters, Natasha and Jazmyn, suffered serious neurodevelopmental harms from sodium valproate, a medicine Astill took while pregnant with no idea of the potential lifelong effects on her children. The twins, now 20, have autistic traits and suffer from congenital malformations and difficulty with walking and fine motor skills, as well as other medical problems. Decades passed before many countries urged against prescribing the medicine in pregnancy. And still, Astill says, little has changed. In New Zealand, “we have not got any postmarketing surveillance around pregnancy.” She founded an advocacy group in 2015 to lobby for more research on drug effects and for support for families like hers.
“I honestly don’t understand,” says Rebecca Bromley, a pediatric neuropsychologist at the University of Manchester who has assessed and cared for affected children like Natasha and Jazmyn. “As soon as a medication is approved, someone [should be] appointed to immediately follow the first births.” This should include the launch of multiple independent studies, she says, to provide comprehensive information.
Over the years, some researchers have tried to fill in the data gaps, one puzzle piece at a time. At UCSD, perinatal epidemiologist Christina Chambers was dissatisfied with the usual evidence on drugs in pregnancy, which generally comes from animal research. Companies often give pregnant animals doses many times higher than those prescribed to people, looking for effects on fetal growth and survival, and major malformations in the offspring. The result, Chambers says, is better than nothing, but such findings often don’t translate neatly to people.
So in the late 1990s, she and her colleagues launched a nationwide registry that has enrolled thousands of pregnant people who use various medications (or sometimes no medication at all) to treat asthma, high blood pressure, depression, and many other conditions. Participants agree to be called regularly and to release their and their children’s medical records, allowing researchers to hunt for differences between those who are and are not on a certain medicine. Among other findings, the MotherToBaby registry reported that flu vaccines and adalimumab, a drug used to treat rheumatoid arthritis and Crohn’s disease, aren’t associated with poor pregnancy outcomes.
Some physicians also have established registries for patients with specific conditions. Mahadevan has so far recruited 2000 pregnant people for PIANO, the Pregnancy Inflammatory bowel disease And Neonatal Outcomes registry, and among other findings has documented that when disease flares, patients have a higher risk of miscarriage. Her registry recently added annual questionnaires to gather information on participants’ children until they turn 18.
Registries, Chambers says, provide an early warning that drugs may cause problems— or reassurance that their risks appear low. But registries can also suffer from sluggish enrollment of patients on a hodgepodge of therapies and limited funding. “It takes 20 years to collect vaguely useful data” from registries, says Clowse, who despite her misgivings runs one for rheumatic disease in pregnancy that includes about 800 people. She sees an urgent need to give better guidance, especially for the sickest patients navigating pregnancy—which in her practice includes those with lupus who are at high risk of very early delivery.
One was Beugre, whose health took a dive when she was 17 weeks pregnant. An immunosuppressant called azathioprine, which is used in pregnancy, risked harming her liver, so Clowse cut the dose. Soon after, at her sister’s October birthday party, Beugre’s skin began to itch again. Within days her eyes were swollen each morning when she awoke, and one day she couldn’t open her right eye at all.
Beugre raced to the hospital, where she received high-dose steroids. And then came the difficult question: What next? Inflammation from the disease, she was told, could spread to the placenta and kill her fetus. Clowse pinned her hopes on another lupus treatment: rituximab, a monoclonal antibody first approved in 1997 that tamps down the immune system. But Clowse was nervous, too, because rituximab can interfere with the development of an important class of immune cells, called B cells, in the second half of pregnancy. Beugre was teetering on that line.
“We had to make a pretty rushed decision,” Clowse says. “Every week of delay would put the baby at risk.” Beugre received two infusions, which helped, and Clowse fervently hoped they would carry her patient through the rest of her pregnancy. After she’d delivered her baby boy, Beugre could get another course of rituximab—or newer medications, whose effects on a fetus are unknown.
For Clowse, walking that tightrope, as she’d done many times before, was immensely frustrating. Her registry can’t offer quick facts about new drugs. “We need some pregnancy-focused drug trials to answer important questions on new therapeutics,” she says.
As Costantine has learned firsthand, however, running traditional trials in pregnant patients is littered with obstacles. He focuses on preeclampsia, a life-threatening condition of pregnancy marked by soaring blood pressure that’s cured only by delivering the baby, often far too early. Desperate to find a better treatment, Costantine began more than a decade ago to study a cholesterol drug called pravastatin, first approved in the United States in 1991. It looked promising: Experiments in rats by several groups showed that pravastatin reduced the risk of preeclampsia without apparent downsides. Beginning in 2012, FDA permitted pilot studies, and over time Costantine enrolled 40 pregnant patients who’d had severe preeclampsia in a prior pregnancy, leaving them at high risk of a repeat. Nine of 20 in the placebo group developed the condition, compared with two of 20 in the treatment group. But the numbers were too small to declare the drug effective.
In 2018, Costantine received funding from the National Institutes of Health for a definitive trial of more than 1500 patients, but FDA told him he could include no more than 50. The agency’s concern, Costantine says, stemmed from decades-old data from rats suggesting that at doses six to 10 times higher than what he is studying, the drug can affect part of the developing brain. FDA officials have asked Costantine to repeat the rat studies, which he says would cost more than $1.5 million and add little value given that much can be learned from the babies born in his studies.
Those children are now 2 to 7 years old and by all appearances are healthy; Costantine presented an update on 30 of them at a meeting in February, covering verbal, spatial, motor, and other skills. In fact, he says, the children born to patients who got pravastatin have had slightly better outcomes, which he speculates are partly because they were less likely to be born prematurely. Costantine feels caught in a catch-22 that, he says, encapsulates much of the field. “The best way to treat the mothers is to have good evidence,” he argues. “The only way to get this evidence is to do research.”
There needs to be a cultural shift in viewing pregnant people as medically complex, rather than vulnerable, needing protection.
- Maged Costantine
- Ohio State University, Columbus
FDA’s Yao declined to speak about the pravastatin case but acknowledged the agency’s balancing act. “We just don’t want to do the wrong thing,” she says, adding that solid preclinical data are crucial before testing a therapy on pregnant people. At the same time, “I fully understand the flip side: Being too conservative can also hurt.”
Moving pravastatin, a drug approved long ago, into pregnancy trials has been hard enough. With experimental therapies, the hurdles loom even higher. There can be “a huge liability issue” if a pregnant study volunteer has a baby with a birth defect, for example, says Marie Teil, a clinical trialist with experience in research ethics. She was hired by UCB Biopharma, a pharmaceutical company in Belgium, to help it learn how to study its products in pregnant and breastfeeding people. And there are ethical concerns, too. Teil questions whether experimental treatments, whose effectiveness is by definition unproven, should be offered in pregnancy given unknown risks to the fetus.
But, Teil says, other avenues are available for learning. After joining the company in 2013, she focused on a UCB therapy called certolizumab pegol (Cimzia), first approved in 2008 for rheumatoid arthritis and other immunologic conditions. Lab findings suggested it might not cross the placenta. To prove that in patients and assess whether the therapy could pass into breast milk, the company launched two human studies of pregnant and breastfeeding patients, enrolling only those already taking certolizumab. Researchers tested participants’ blood during pregnancy, umbilical cord blood at birth, breast milk, and blood from the baby, by heel prick, at 4 and 8 weeks of age.
The studies, which each included about 16 volunteers, took more than 2 years. Ultimately, researchers found that “no to minimal” drug reached breast milk or crossed the placenta. Europe and the United States added this new evidence to the drug label. Now high on Teil’s todo list is keeping track of those who become pregnant during any UCB drug trial, though she says she does not expect the company would continue them on experimental medications. Those patients, who may have been exposed to a new therapy in early pregnancy, could offer valuable clues about drug safety for pregnant people and their children.
UCB’s evolving processes come amid a broad effort to spark change. The push began in earnest about 5 years ago, with the congressionally mandated Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC, pronounced “preg-lac”). PRGLAC’s members, generally physicians and scientists with expertise in maternal and pediatric health, many at government agencies, delivered a laundry list of recommendations to the Secretary of Health and Human Services and Congress in September 2018. The list included no longer requiring paternal consent for participation in studies, funding programs to study drugs that pregnant and breastfeeding people commonly use, developing a strategy to mitigate liability risk for companies, requiring investigators to justify excluding pregnant and breastfeeding patients from clinical trials, and boosting lab research on drugs in pregnancy.
Some of PRGLAC’s bullet points call for a sea change. But others are what advocates describe as “low-hanging fruit,” and some are beginning to be implemented. In 2021, moved partly by PRGLAC’s urgings, the National Institute of Child Health and Human Development committed $27.5 million over 5 years to create the Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub. Among the projects it supports is one mining electronic health records to study opioid exposure in pregnancy and babies after birth, and another that will probe antibiotics in mouse models and pregnant and breastfeeding patients and their babies. MPRINT and the Bill & Melinda Gates Foundation are also working to develop “virtual pregnancy” computer models that forecast how drugs will behave.
FDA, meanwhile, recommended in 2018 draft guidance that when a patient gets pregnant during a trial, she be followed and even offered the chance to continue on the study medication if that had been her assigned group. “We have tried very hard to improve in that space,” Yao says of FDA’s policies. Among other efforts, the agency is also trying to craft strategies to better communicate risk and research findings to physicians caring for these patients.
But guidance can accomplish only so much, Costantine believes, noting the exclusion of pregnant people from COVID-19 vaccine and treatment trials. “There needs to be a cultural shift in viewing pregnant people as medically complex, rather than vulnerable, needing protection,” he says.
And even if the drug safety picture sharpens in the coming years, pregnant patients will still face the intensely personal question of how much risk to accept. “What do women actually care about?” Clowse asks. It’s widely agreed that certain medications, such as thalidomide and valproate, should be avoided in pregnancy. But at times, some risk to the fetus may be worth an outsize benefit to the mother. Protecting her can help, and even save, her baby, too. Clowse says her patients “want their child to be pretty healthy. Do they have to be perfect? Are there children who are perfect?”
For Beugre, the balancing act persisted through pregnancy, but winter proved far less fraught than fall. She continued taking the steroid prednisone, whose long-term effects on a child’s health, if any, are unknown—like nearly all drugs’. Her dose, 12.5 milligrams per day, was a notch higher than ideal in pregnancy. Mindful of the tightrope, Beugre chose not to increase it when a modest flare caused hair loss and joint pain. But she wasn’t comfortable lowering the dose, either, aware that more serious flares could harm her fetus. “I have to go off my own intuition of what I can handle,” she says.
And she has crossed the finish line. On 16 March, Noble Saleem Beugre-McQueen was born after more than 38 weeks gestation, to a mother exhausted, delighted, and relieved to have made it safely through pregnancy.