“A common concern is that we shouldn’t ‘experiment’ on pregnant people—but the reality is that we already are,” Bilinski said. “Every time a pregnant person takes an untested medication it’s an uncontrolled experiment. The difference is: in a trial, we learn from it.”
For as long as there have been randomized controlled trials evaluating drug safety, pregnant people have largely been excluded, Bilinski explains. That stems from a place of good intentions, particularly in response to the thalidomide tragedy in the 1950s.
Thalidomide was developed by a German pharmaceutical company and prescribed for morning sickness, although it was never tested on pregnant women. After thalidomide was approved in Europe, at least 8,000 babies were born with severe drug-related birth defects. This led to stricter drug safety regulations—including in the US where thalidomide was never approved—that required evidence of safety and efficacy before market approval.
Memories of thalidomide also informed the exclusion of all women of childbearing age from RCTs. Even though that policy was partially rolled back in 1993, pregnant people are still rarely included in trials. “That might feel like the safest choice—but our study shows that, when a drug is beneficial, excluding pregnant people from research can actually cause harm,” Bilinkski said. “Without trial data, both pregnant patients and their providers often hesitate to use potentially helpful medications due to uncertainty about safety.”
In their study, Bilinski and her team quantify both the potential harm of conducting trials during pregnancy (if the drug is harmful), and the potential harm of not conducting them (if the drug is beneficial but goes unused or is used without understanding the risks). This framework helps shift the conversation from theoretical fear to evidence-based comparisons.
In the case of thalidomide, had it “been tested in a completed RCT with 200 treated participants, about 33 children would have experienced severe adverse effects,” the researchers write in their study. Meanwhile, discoveries from the trial “would have prevented 8,000 thalidomide-related birth defects or 99.6% of all thalidomide-related birth defects from 1956 to 1962.”
Similarly, the researchers show that if trials for COVID-19 vaccines had included pregnant participants, and if their vaccination rates had been similar to those of non-pregnant women of the same age and state, a projected 20% of COVID-19-related maternal deaths and stillbirths in the United States would have been prevented from March to November 2021. That’s roughly 8% of all maternal deaths and 1% of all stillbirths during that time.
Researchers also studied dolutegravir, an antiretroviral medication for HIV, for which initial observational data suggested potentially severe adverse effects for infants. This led the World Health Organization to caution against its use in women of childbearing age. However, additional observational studies did not find this risk for infants, and in 2019, the WHO reversed its advice and began recommending the drug for everyone, including women of childbearing age.
But even as the recommendations have changed, fewer women today are using dolutegravir compared to other groups. Researchers estimate that the low uptake among women aged 16-49 has led to 16 additional deaths in the survey sample. After extrapolating to all women receiving antiretroviral therapy between the ages of 15 and 49, researchers found that the avoidance of dolutegravir could have contributed to 3,228 deaths. Meanwhile, a large trial sample size “could have detected adverse effects had they existed,” the team writes.
“We have already embraced randomized controlled trials as the gold standard for learning about drug safety and efficacy in the general population. We hope this paper emphasizes the importance of providing that same standard of evidence during pregnancy.”
