In stories about medication abortions, we often give mifepristone a starring role. We call the dashing biochemist who developed it “the father of the abortion pill,” noting his youth spent in the French Resistance and his glamorous, Vanity-Fair-worthy flings. We see it in the headlines pretty frequently, dragging its trusty sidekick misoprostol in tow. Later this month, a Trump-appointed judge in Texas may well ban it from the sanctioned market by ordering the Food and Drug Administration to overturn its approval.
So it might seem surprising that American abortion providers are responding to that threatened prohibition by preparing to forego mifepristone and use misoprostol alone. How could that be? Wasn’t mifepristone the abortion pill, the critical tool for ending a pregnancy in the first trimester? If you can get the job done with one drug, why have we been using a combination of two?
It turns out our narrative has been backward. Biologically speaking, mifepristone is the sidekick, and misoprostol the superhero, mifepristone the opening act while its counterpart carries the show. “If you had to choose only one, you would choose the miso,” explained Beverly Winikoff, president of the research group Gynuity Health Projects, who helped develop the World Health Organization’s guidelines for medication abortion. Both regimens — either the two drugs together, or just misoprostol — are extremely safe. And they’re both very effective. Chances are, taking misoprostol alone will work to end a pregnancy early on, but it’s likely to come with more discomfort, cramping, and nausea.
That doesn’t mean reproductive health experts aren’t worried about the possibility of mifepristone’s approval being revoked. They’re very worried. “Devastating, baseless, and potentially catastrophic” are the words that epidemiologist Heidi Moseson used to describe that scenario. The two-drug combo is the standard of care, the very best recipe in the current pharmacopeia if your country’s medicine cabinet is well-stocked. The lawsuit, brought on behalf of anti-abortion groups, claims that the FDA ignored potentially harmful side effects when it allowed the drug onto the market 23 years ago. But the decades’ worth of data tell a very different story, revealing a remarkably low-risk drug — with efficacy above 95%.
The data about how well misoprostol works alone, on the other hand, have been more variable. Some studies show its efficacy rates right up there above 95%, too. In others, that measure has been closer to 80%, leading to a general consensus that it’s less effective on its own. It’s a great alternative, experts say — well-studied, recommended by the World Health Organization in settings where mifepristone isn’t available — but an alternative just the same. “An excellent second choice,” Ushma Upadhyay, a reproductive health researcher at the University of California, San Francisco, called it.
The dynamic between this dynamic duo was shaped not only by biology, but by cultural history as well. To understand the messier data on using misoprostol alone, you have to delve not just into what each drug does in the body but also how it traveled across the world. Mifepristone started out as a glimmer in the mind of our dashing French biochemist, Étienne-Émile Beaulieu, in the 1970s. Disturbed by stories he’d heard of desperate women poking themselves with sticks to provoke miscarriages, he set out to find an anti-pregnancy molecule. His project was about uncovering a safer, easier abortion method from the get-go. What he imagined was being able to block the hormone progesterone, which acts as a kind of signal during pregnancy for the uterus to thicken its inner lining, forming a nest rich in blood vessels. Even after implantation, the developing pregnancy keeps lodging itself more and more deeply there, receiving the nourishment it needs to grow.
Stop progesterone from being received, and you can interrupt the formation of that nest, loosening the pregnancy from its foothold and obstructing its growth. And in 1980, at Beaulieu’s request, a chemist at a pharmaceutical company synthesized a molecule that could do just that.
Misoprostol, on the other hand, started out as a drug to treat gastric ulcers. It was known to have serious side effects during pregnancy: It’s a lab-made version of one of the body’s own naturally-occurring compounds, which can help stimulate uterine contractions — an essential part of labor, but a possible cause pregnancy loss if it occurs earlier on. “There was a warning label on the drug saying that if you took this while you were pregnant, it could induce a miscarriage. So if you’re pregnant, don’t take it,” said Moseson, the epidemiologist at Ibis Reproductive Health, a nonprofit research group. “And feminists in Brazil in the 1980s sort of saw an opportunity in that warning label and began using the medication to induce abortions with great success.” That knowledge began spreading throughout the country, and then elsewhere in Latin America, then across the world.
It involves more discomfort than the two-drug regimen because of the physics involved. Take mifepristone first, and the contents of the uterus have already begun to detach a little from the lining. Take only misoprostol, and the contractions have to do the work of both getting those tissues dislodged and expelled. You may have to take more than you would in the two-drug combo, upping the likelihood of diarrhea and vomiting. It can also take longer for the body to push out those tissues.
Plus, some tissues can remain in the uterus for weeks — and that can complicate the data. In clinical trials, if a patient hasn’t fully passed all that material after a week or two, they might be offered an intervention, and have it suctioned out. Many are anxious to have the experience over with, and in that case, the miso-only abortion might be logged in the literature as having “failed.”
In places where that kind of intervention isn’t accessible, the efficacy of misoprostol alone is often higher. Take, for instance, a project to provide the drug to those who needed it in refugee camps on the border of Thailand and what’s now officially Myanmar. “We had 918 people who obtained abortion care through this program over a three-year period, and over 96% of them were not pregnant after four weeks from initiating the process. That was much higher efficacy than what had previously been reported,” said Angel Foster, professor and abortion care researcher at the University of Ottawa.
The discrepancy could arise in part because of the off-label history of the single-drug regimen. Patients have taken various doses at various time intervals through various routes of administration, their care determined a success or a failure at different numbers of weeks. That makes it hard to compare one study to another. Researchers have tried: In 2019, a team reviewed the evidence from 38 scientific papers on the subject, and found an overall efficacy of 78% for misoprostol alone. But nearly half of the conglomerated group of study participants came from older research projects, in which they had waited 12 or 24 hours between doses of misoprostol. Now, the recommendation is to keep taking doses three hours apart, until the tissues are expelled. “So about half of that participants in that study come from a regimen that is no longer recommended, that is now known to be less effective,” Moseson said.
In a way, that’s heartening. Misoprostol alone may be more effective than we’ve given it credit for. Then again, some of those studies provide a window into what may emerge from this judge’s decision. What they show are tough real-world scenarios, in which doctors and patients are making do, managing abortions with what’s available.
In June 2020, the Covid pandemic disrupted mifepristone supply chains from India, and Aid Access, the gray market provider of abortion pills, began sending out misoprostol alone to Americans. It worked well, showing 88% efficacy overall, and 97% in those who had a known outcome four weeks out. What does that mean, you might wonder, for the outcome to still be unknown after a month? “They did take the misoprostol— that is confirmed. But they also hadn’t yet confirmed a complete abortion, nor have they gone to a clinic for surgical intervention,” explained Dana Johnson, a PhD candidate at the University of Texas and an associate research scientist at Ibis Reproductive Health. “At four weeks, the literature tells us, they could still be self-managing, they could still be passing the pregnancy… they themselves are unsure.”
One wonders what those four weeks were like for those patients. Already, the experience of getting the standard-of-care is difficult, with patients required to drive from restrictive states to non-restrictive ones. Switching to misoprostol alone could require those trips to be longer. “They have jobs. They have children at home that they’ve asked a friend to watch for the day,” said Upadhyay. “They have to get back. ”
Even if it weren’t for the more complicated efficacy data of misoprostol alone — the nitty-gritty questions about study design and surgical intervention and what counts as success versus failure — perhaps most important are the patient’s comfort and sense of security. People will be seeking medication abortions anyway, whether through regulated markets or less sanctioned ones. “I and everyone else should want to live in a world where the abortion process is as comfortable as possible, and we minimize side effects and pain,” said Foster. There are places where misoprostol is what someone can get, she went on, because it’s cheaper, more accessible, less tightly controlled. “Everything being equal, of course, I would always recommend mifepristone and misoprostol over misoprostol alone. But we don’t live in a world where everything is equal.”