The program meant to help pregnant people safely find prescriptions to take has stalled
Elisabeth Donnelly realized she was pregnant as New York City went into its first COVID-19 lockdown. She ordered a test to be delivered with her groceries from the local supermarket, and it confirmed her suspicions.
The Brooklyn resident, who is in her thirties, was taking the antidepressant bupropion, marketed as Wellbutrin, as well as Xanax as needed. Before she talked to her psychiatrist, she asked her friend’s husband, also a psychiatrist, what to expect from the appointment.
He told her that her doctor would likely suggest she go off her medications to protect her pregnancy. That’s exactly what happened, she said—though the psychiatrist suggested she switch to Prozac as an alternative. She’d taken the SSRI before and knew it wasn’t for her.
“My options were Prozac or cold turkey,” she says. “And I actually really preferred cold turkey.”
Donnelly, who had dealt with pregnancy loss twice before, took the psychiatrist’s advice and went off her meds in the earliest, most uncertain days of a world-changing pandemic that was reshaping her city.
People who are pregnant or trying to get pregnant face an invisible barrier that substantially impacts both their quality of life and their ability to make informed decisions about their own health: They’re what are known as “drug orphans.” That means there’s little evidence about the safety and efficacy of medications during pregnancy and even after it.
That deficit is the result of a simple fact: Pregnant and lactating people are proactively excluded from clinical trials. As a result, the body of knowledge that doctors rely on when advising their patients about which medications are safe during pregnancy and while breastfeeding a child is based on a combination of preclinical studies in animals and evidence-gathering from other pregnant people who were taking the medications before or during pregnancy.
“If you’re pregnant and you go to the doctor, whatever you have, whether it’s a cold or a serious condition, if there’s a drug for it, the doctor who’s offering it to you probably doesn’t have any research to rely on unless it’s been out for a while and there’s reports on how it’s been used clinically,” says Marsha Michie, a Case Western Reserve University bioethicist. “You basically get to be a research subject, even though you’re a clinical patient.”
Creating better evidence for pregnant people will involve a “major paradigm shift,” as a coalition of experts from Europe and the U.S. wrote in an FDA blog post last summer. Until 2019, pregnant women were classified as vulnerable persons under U.S. guidelines on human subject research, which meant they couldn’t be included in clinical research. The change has to go beyond any single rule, experts say.
After giving birth in October 2020, Donnelly went back on Wellbutrin, at a higher dose than she was previously taking. She hasn’t forgotten the experience of having to suddenly go off her medication at such a stressful moment.
“It’s messed up, and it puts women in a difficult position in regards to the life of the child or their ability to function,” Donnelly told Fortune over the phone as she played with her daughter, Porter, now 2 years old. “It’s not discussed enough.”
All this isn’t to say that there is absolutely no evidence for a doctor to rely on when treating a pregnant person, says Rachel Saunders, a University of Kentucky ob-gyn. “We do have a lot of data based on patients taking medications,” she says. That data is documented in a variety of “pregnancy exposure registries” around the country.
Those registries provide data on safety and, to some degree, on dosing and efficacy. But they don’t all collect the same information, and the data they include is rarely representative of the whole population, one 2021 review of the issue noted. And pregnancy is physiologically very complicated, which means a dose that works well in the first trimester may not be enough—or may be too much—in the third.
“Clinical trials are the way that we get…really good, reliable information,” says Michie. She and many of her colleagues advocate for a change in policy that presumes pregnant people should be included in late-stage clinical trials unless there is a specific reason—such as evidence from animal trials showing harm to what’s termed the “maternal-fetal dyad”—justifying their exclusion.
The status quo has been changing, though slowly. FDA labeling requirements have changed in recent years to mandate that drugmakers include more complete information about a drug’s potential risks while pregnant or breastfeeding. But without better evidence, that labeling still doesn’t represent a fully informed picture of a drug’s safety and efficacy.
The U.S. government made strides toward changing the research paradigm with the establishment of a federal Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) in 2016. In 2018, the task force released a report with 15 concrete recommendations and then established an implementation plan for those recommendations.
One major change recommended by the task force has already been implemented: removing pregnant women from the “vulnerable persons” category of the Health and Human Services research regulations known as the Common Rule. That removal allows them to choose to participate in federally funded clinical trials where appropriate. But the work remains incomplete: FDA-specific trial rules don’t evenly reflect the change in status of pregnant women, which means their practical inclusion in research is still very limited, notes Michie. “There are still lots of exclusion criteria for research sets governed by the FDA and also at lots of local institutions,” she says.
The PRGLAC implementation plan was released in August 2020, during the second wave of COVID-19 infections in the United States.
That’s where the progress stalled. PRGLAC’s charter expired in April 2021, eight months later, and wasn’t renewed by Health and Human Services Secretary Xavier Becerra. As of this writing, the charter is still lapsed.
The COVID-19 pandemic laid bare the problems with leaving pregnant people out of drug development. Coalitions of experts from around the world repeatedly highlighted the need to include them in clinical trials of COVID-19 treatments and vaccines, almost from the beginning of the pandemic. But when the Pfizer-BioNTech and Moderna vaccines first became available in the United States, they didn’t include data specific to pregnant people. Like the drugs before them, they instead relied on evidence gathered from those in the cohort who chose to get vaccinated to gather information. That evidence did, in time, generate enough data for the FDA to recommend pregnant people get the vaccine in April 2021.
In the four-month gap between when the vaccines were first granted an Emergency Use Authorization for adults and when the FDA recommendation for pregnant people was made, thousands of pregnant people individually weighed the risks and chose to get vaccinated. The vaccine undoubtedly protected them and their pregnancy, as we now know, and even then, experts were pretty sure it would be the case. But the safety and efficacy data we have now for pregnant populations is the result of their bravery.
When the Omicron wave came crashing over the country months later, a mere 40% of pregnant people were vaccinated. Misinformation about an untrue link between the vaccines and fertility issues was slowing progress in vaccinating adults and kids alike. This incident illustrates the high societal stakes of leaving pregnant people out of clinical research. Changing the paradigm requires special focus, lawmakers say: “Oversight from a dedicated group of experts is needed to continue to make progress in establishing therapeutic options for pregnant and lactating women,” reads a January letter to Secretary Becerra signed by a group of more than 60 bipartisan legislators. The letter called for PRGLAC to be reinstated or for another advisory committee “with a similar range of expertise” to be established.
That dedicated group of experts would oversee and advise the complicated work of figuring out how to proactively include pregnant people in all clinical research and implement the other PRGLAC recommendations that remain uncompleted.
“The Biden administration has been very responsive to working with us on health concerns affecting women and children, and I look forward to working with them more on this important issue,” said Rep. Lois Frankel, cochair of the Democratic Women’s Caucus and a cosignatory to the letter, in an email to Fortune.
The Department of Health and Human Services did not respond to a request for comment.
Not including pregnant people in clinical trials deprives them of safe access to new drugs, wrote two University of Pittsburgh medical doctors in an expert review published last June. In the past 20 years, they wrote, “new therapeutics for chronic conditions in men and nonpregnant women have vastly expanded the options for physicians in the treatment of diseases, especially in the area of biologicals.” But not for everybody: “These therapeutic options have not been studied in pregnant and lactating women; these women are therapeutic orphans.”
All of this puts women and other people who might get pregnant—in other words, about 76 million Americans—in a difficult position, especially if they’re among the 60% of Americans living with at least one chronic condition.
Sarah Liss had headaches all her life. In her late twenties, they swelled into regular migraines, one or two a month. By her early thirties, the Toronto resident lived with three or four debilitating migraines per week. The pain would start as a nausea-inducing dull ache, crescendoing to a roaring fire of pain dominating the left side of her head, wrapping around from her eye to her ear.
The only thing that dulled the roar—sometimes, with luck, even silencing it—were a class of medications called triptans, which work by influencing the brain’s serotonin receptors. “The only way to avoid being totally debilitated for a few days at a time was triptans,” Liss says.
Liss accepted that she’d be on one or another of the class of medications all the time, and they became part of her life. But then she decided that she wanted to carry her family’s second child after her partner carried their first.
She went to a headache specialist at Women’s College Hospital in Toronto who told her she should stop taking triptans for the duration of her pregnancy. “She recommended taking Tylenol with caffeine and doing everything I could possibly do to focus on not getting migraines,” Liss says.
She did so, holding back her debilitating condition with a combination of over-the-counter medications, obsessive focus on her lifestyle, acupuncture, and luck: Like her mother, who also experienced migraines throughout her life, the hormonal shift of childbearing seemed to make her headaches less frequent and severe, she says. On the few occasions when it was as bad as it had been before her pregnancy, she knocked herself out with Gravol and slept in a dark room until the worst was over.
The process of getting pregnant and carrying a pregnancy took nearly two years of “hypervigilance and anxiety,” culminating in the birth of Liss’s son, now 4 years old. After his birth, her migraines returned, and she started taking Imitrex, the oldest of the triptans, which has been shown to have a short half-life but is less effective than the triptans she was on before trying to get pregnant. She made that choice because she was breastfeeding, and because Imitrex had been on the market longest there was more information about it than the other drugs. “I was like, well, this seems like at least there’s data,” she says.
“We should not expect pregnant persons to make significant sacrifices in a way we don’t expect other persons to,” says Ruth Farrell, a Cleveland Clinic ob-gyn and Michie’s coauthor on an academic article from July 2020 that called for pregnant people to be ethically included in trials of COVID-19 drugs and vaccines.
Much of the concern about finding a way to include pregnant people in clinical trials stems from worry about the harms of trials, says Farrell. But “we have to turn that on its head a little bit,” she says. “We have to think about what are the harms of having no trials, and the harms of exclusion.”
Saunders, the University of Kentucky ob-gyn, counsels patients who are pregnant or planning to become so on an individual basis. She and her patients review all of their medications and discuss what’s known about the potential risks of each as well as alternative medications or treatments that might be safer. Ideally, she says, “you want to talk to that patient in the preconception stage.”
The doctor says her patients are generally keen to do whatever they can to protect their pregnancy, but there are limits to the advice she can give them. For some drugs, which are FDA classified as potentially risky, there’s only so much she can say.
“I always tell patients, my number one priority is keeping you safe,” she says. “Because if you’re not safe, your baby’s not safe.”
Correction, February 14, 2022: This article has been updated to reflect the letter sent to Secretary Becerra was signed by bipartisan legislators.
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