For decades, it's been taboo to test medications on pregnant women. But doctors, patients, and public health officials are increasingly arguing that it's unethical not to include them in research. So new ideas for changing the research culture are emerging.
Doctors, ethicists, and drug industry leaders laid out several concrete suggestions for addressing the problem in interviews with STAT and in presentations to a federal task force studying the issue.
The scope of the problem is clear: Of the thousands of research studies in the U.S. recruiting women right now, just a few dozen specifically include pregnant women. And while the other trials technically could enroll pregnant women — after meeting certain requirements — they often don't.
"It's absolutely possible to do studies in pregnant women," Dr. Catherine Spong, an obstetrician who is leading the National Institute of Child Health and Human Development task force. The task force will present its recommendations to the federal health department next year.
In the meantime, here's what experts have suggested might help.
Make clear it's ethical to do research in pregnant women
The first step to improving research on pregnant women: Talk about it like it's OK to do it.
"Research with pregnant women is the ethical thing to do. Not doing the research is unethical," said Dr. Anne Lyerly, a physician and bioethicist at the University of North Carolina, Chapel Hill.
The major hesitation, of course, is that exposing pregnant women to medications that haven't been proven safe can put them or their fetuses at risk. No one wants to risk another tragedy like thalidomide, which was widely prescribed to pregnant women for morning sickness in the 1950s and caused devastating limb deformities in their babies.
But experts say it's crucial to recognize that without research, every pregnant woman who needs to take a medication is doing so blindly. That, too, is a risk to pregnant women and fetuses.
There are signs that the conversation is starting to change, including the creation of the federal task force. Movements like the Second Wave Initiative — a collaborative academic effort — have also worked in recent years to advocate for ethically and scientifically responsible ways to include pregnant women in medical research.
"There's a growing recognition that keeping pregnant women out of the research agenda does not help them in the end," Lyerly said.
Another emerging argument: The lack of research isn't only unethical — it's also unjust. Public tax dollars fund biomedical research, but pregnant women — who pay into the system — don't benefit.
Assume women should be included, not excluded
Right now, most research trials in the U.S. are run with the assumption that all pregnant women will be excluded. Some even require women of childbearing age to use two forms of contraception during the study period.
That's due in part to a regulation known as the common rule, which governs all research involving human subjects. Pregnant women are currently listed as an example of a "vulnerable population" in guidance for researchers, along with prisoners and people with diminished mental capacity. The designation is designed to protect people who might be at risk of being pressured into participating in a trial.
In January 2017, the government enacted changes to that language which would remove pregnant women as a de facto example of a vulnerable population. (Depending on the trial, they could still be deemed a vulnerable population.) To include pregnant women in a study, researchers will still have to meet a specific set of requirements, including demonstrating that the trial has the potential to directly benefit a pregnant woman or fetus — and if it doesn't, that the trial poses nothing more than a minimal risk to the fetus.
Advocates for the change hope it will begin to shift the culture in the research community. Instead of assuming pregnant women should be excluded, they want scientists to assume they should be included — unless studies in pregnant animals suggest the drug might pose a risk.
The new rule is set to go into effect on Jan. 19, 2018. But there could be a hiccup: In October, the Trump administration proposed delaying the rule for another year. That proposed delay is currently being reviewed by the budget office.
The Department of Health and Human Services said the agency can't comment on items going through the rulemaking process until they've been published in the Federal Register. The proposed delay hasn't yet been published there.
Launch more retrospective studies on pregnant women
To sidestep some of the clinical trial hurdles, researchers could work to collect more data from pregnant women who are already taking medications. They could also look at data sets on children whose mothers took medication while pregnant.
While such retrospective studies can't be used to test a potential new therapy, they could give doctors a better, if limited, idea of whether already-approved drugs are safe for pregnant women.
"There's a lot of research that can be done without imposing any risk on [pregnant women] whatsoever," said Lyerly. "It's really no-brainer research."
Experts stress that retrospective studies shouldn't be used in place of randomized controlled trials. They only show correlations, not causation. So it's impossible to tease out whether a medication used during pregnancy is responsible for any harm to the woman or her baby.
Say 10,000 women take an anti-seizure medication for epilepsy during pregnancy, and 6 percent of babies born to those women have a birth defect, compared to 3 percent of babies born to the general population. Is it the medication that's connected to that increased risk, or is it physiological differences in women who have epilepsy? There's no way to tell for sure from this kind of study.
Still, experts agree: Any evidence is better than no evidence at all.
Make the most of pregnancy registries
Many drug companies are actually already running that type of study. ClinicalTrials.gov currently lists dozens of pregnancy registries — many of them owned and operated by drug companies — that are recruiting pregnant women who have taken a wide range of medications, from narcolepsy drugs to the flu shot. The researchers gather data on the women and the health of their babies, which they could mine to try to find correlations.
Such analyses could offer insight into medication safety during pregnancy. But the data quality from those registries is variable. To take one example: In some cases, patients report their outcomes. In others, providers report patient outcomes.
Creating a set of guidelines to standardize the data collection could make it more valuable to the public.
Another possible fix the task force is considering: Create disease-focused pregnancy registries, instead of drug-focused registries, which are limited in their scope. That would give doctors an easier way to compare, for instance, outcomes for patients on an array of antidepressants.
Incentivize the drug industry to include pregnant women
If there's going to be more research involving pregnant women, the drug industry is going to need some convincing. Research involving pregnant women poses a set of challenges unlike any other the pharmaceutical industry faces — there are regulatory hurdles, ethical questions, and a complicated calculation of the risks and benefits to both a pregnant woman and her fetus.
"It's really unusual that a drug company is willing to run a trial using children or pregnant women. There's too much liability involved," said Dr. Daniela Carusi, an obstetrician at Brigham and Women's Hospital in Boston.
And on top of that, researchers are working with a ticking clock — pregnancy means there's a particularly short window to locate potential participants, enroll them, and run the study.
At a November meeting of the federal task force, Robert Ternik, a senior research adviser for the drug maker Eli Lilly, said pregnancy is "pretty much a universal exclusion" for randomized, controlled trials of an innovative or investigational new drug.
"Fear is a great motivator," he told the panel.
The task force is looking at a number of ways to overcome that wariness. They're exploring federally funded injury compensation programs, like the one that currently exists for vaccines, to protect drug companies from financial consequences if a pregnant woman or her fetus suffers harm during a trial.
Also on the table: more dedicated funding for research on pregnant women.
Legislation could be a tool to boost research, too. There's interest in looking at whether lawmakers could take a page from the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act, which were signed into law in 2002 and 2003, respectively. They gave drug companies an additional six months of patent exclusivity if they ran pediatric studies to improve labeling on medications commonly prescribed for kids.
The legislation has fostered significant progress in pediatric drug research. Since 2002, the National Institute of Child Health and Human Development has sponsored dozens of clinical trials involving children, some of which have led to labeling changes to add a specific pediatric dose for drugs already on the market. The agency has also supported the Pediatric Pharmacology Research Units, a research network that has carried out more than 260 pediatric studies.
If all the pieces fall in place and more studies do open up, researchers will have to convince a population that's been left out of research for decades to participate in studies.
Some experts think that won't be a big problem; others see low enrollment in some of the studies that have sought out pregnant women as a sign that recruitment could be difficult.
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