Randomized controlled trials should include pregnant women

“Well, we don’t have as much evidence as we would like on steroid use during pregnancy,” the obstetrician warned my co-author, Natalia Emanuel, as she wrote a prescription for inhaled corticosteroids to help treat a respiratory illness that was causing chronic shortness of breath. “But having difficulty breathing isn’t good for your baby either. It’s really up to you: You decide whether you feel you need the inhaler.” 

Natalia’s obstetrician was following best practices for “shared decision-making” around medication use in pregnancy. But it was not a comforting message. While inhaled steroids — like all FDA-approved medications — were tested in rigorous randomized controlled studies before distribution, these studies didn’t include pregnant participants. So uncertainties lingered about the impact on her unborn son. 

More than 90 million women in the U.S. have given birth at least once. Still, pregnant participants are routinely excluded from clinical drug trials testing the safety and efficacy of medications. Excluding pregnant participants from RCTs is intended to prevent harm to them and their children. But it may, in fact, achieve the opposite: This practice exposes more people to potentially bad outcomes from untested medications and simultaneously allows fewer people to access the benefits of medical advances. 

Natalia was not alone in having to make medical decisions without the benefit of evidence. Over recent years, we’ve talked with dozens of women and clinicians — many of whom had even less information than Natalia did to guide difficult decisions for themselves and their babies. Is it best to risk a relapse in depression by stopping treatment, continue bupropion, or switch to SSRIs that worked poorly in the past? Better to stop anti-epileptics or risk seizures?

Since the early 1960s, the FDA has required pharmaceutical companies to provide evidence of drug safety and efficacy prior to receiving FDA approval. These regulations were catalyzed by thalidomide — an anti-nausea medication that was marketed to combat morning sickness that caused at least 8,000 babies in Europe to be born with major limb defects. (It was never approved in the U.S., thanks to a single cautious woman working at the FDA.)

In part because of the shadow of thalidomide, this rigorous standard of evidence has always made a special exception for pregnant women. Initially, all women of childbearing age, not just pregnant women, were excluded from drug development RCTs. This policy was relaxed in the 1980s and inclusion of (nonpregnant) women became required in 1993. Yet, pregnancy remains a routine exclusion criterion in drug development RCTs. Our research has shown that fewer than 1% of clinical drug trials of women 18-45 enroll pregnant participants. 

This leads to an unfortunate situation: Once a medication is FDA-approved in the general population, it can still be prescribed during pregnancy, if there is no clear evidence that a medication causes birth defects. And indeed, people take on average five medications during pregnancy. Many of these lack rigorous safety data. Simultaneously, many people choose to forgo medications while pregnant, even when using them may be healthier for both them and their children.

There have been growing calls, in the past few years, to improve the pregnancy evidence base, to revisit the rules, and to recognize that it is high time to protect pregnant people — and their children — through rather than from research. 

In a new academic paper, we added some hard numbers on the unintended consequences of our current short-sighted practices. No RCT was performed prior to thalidomide’s widespread release in Europe. If an RCT had been run in the 1950s, some children — we estimated up to 33 in a well-powered study — would have tragically experienced birth defects in the trial. But even if these weren’t caught in time to end a trial early, preventing medication release would have protected about 8,000 children, preventing more than 99.5% of birth defects that occurred. (Incidentally, to this day, the options for treating debilitating effects of nausea and vomiting of pregnancy remain limited, and it remains a substantial cause of disability and lost work days.)

We also highlighted cases in which pregnant people and their babies may have been harmed by undertreatment. The Covid-19 vaccine RCTs excluded pregnant participants, and as a result pregnant uptake lagged — with devastating effects on maternal mortality. We estimate that including pregnant participants could have averted 20% of Covid-19-related maternal deaths — 8% of all maternal deaths — from March-November of 2021 as well as 1% of all stillbirths during this time.

The “do as you wish” approach to the vaccine also had a risky downside. If the vaccines did, in fact, have unexpected adverse effects, we may not have been able to detect these until after thousands of infants had been affected. That is more babies potentially harmed than would have been exposed through a well-regulated trial.

Despite calls to improve the pregnancy evidence base — from clinicians, advocates, and government groups — the inclusion of pregnant participants in RCTs has remained flat over the past 15 years. Changing this norm will require institutional-level reforms.

For example, a recent report from the National Academies of Science, Engineering, and Medicine suggested reforms for addressing real and perceived liability concerns. An FDA task force proposed reforms related to funding and timelines that account for higher costs and slower enrollment in RCTS that enroll pregnant-participants, compared with standard RCTs. And just as in any drug development clinical trial, we need policies in place to protect those who volunteer in the case they experience long-term health effects.

In the end, pregnant trial participants are much like nonpregnant participants in this respect. Those who volunteer to test medications first are always taking on risks in the hope of benefits for themselves and society from scientific advances. We owe them our gratitude and assurance that we will learn while experimenting on as few people as possible. We cannot currently offer that assurance to pregnant individuals. Each faces a difficult choice — with limited opportunities for others to learn from it.

But we do have hope for a better future. After all, it was less than 70 years ago that drug manufacturers were required to provide evidence of safety and efficacy and less than 35 years ago that drug trials were required to include women. Perhaps in another 70, our stories of lacking rigorous pregnancy evidence will seem just as antiquated.

Alyssa Bilinski, Ph.D., is the Peterson family assistant professor of health policy in the Department of Health Services, Policy, and Practice and Department of Biostatistics at Brown School of Public Health.