Challenges in Medical Research for Pregnant Individuals

In 2021, during the COVID-19 pandemic, Kristin Wall found out she was expecting her second child. Her doctor informed her that information on the safety and effectiveness of the COVID-19 vaccine in pregnant individuals was limited. Although observational data from others who had received the vaccine before knowing they were pregnant suggested safety, the decision ultimately rested on Wall’s evaluation of potential risks and benefits.

Wall, an epidemiologist at Emory University in Atlanta, is in a unique position to assess such health risks. However, her situation is not uncommon; it reflects a broader issue where individuals often face significant medical decisions during pregnancy with inadequate information, as noted by Wall. Pregnancy alters bodily functions, including how medications are metabolized and processed, meaning that a drug might behave differently in a pregnant person than in someone who isn’t pregnant.

Evidence has emerged from a large volume of vaccinations and clinical trials indicating that mRNA COVID-19 vaccines, along with influenza vaccines and others that do not involve live viruses, are generally safe and effective for pregnant individuals. There is also established safety for certain medications, such as some anti-allergy drugs, antidepressants, and antibiotics. Paracetamol, commonly found in products like Tylenol, is generally considered safe, contradicting previous claims made by former President Trump. Yet, other medications, like sodium valproate—a drug for epilepsy—carry known risks during pregnancy.

It’s reported that over 90% of individuals in the U.S. take medications while pregnant. Despite this, the safety and efficacy of numerous drugs—like certain anti-nausea treatments and anti-inflammatories—are still uncertain. This uncertainty arises because many have not been tested on pregnant individuals. Fears of adverse effects and policy restrictions have unfortunately led to the exclusion of pregnant individuals from clinical trials. Consequently, public health recommendations often rely on indirect evidence, such as animal studies and trials involving non-pregnant individuals.

“There’s a massive gap,” Wall states. Together with her colleagues, she has developed trials that safely tested treatments for conditions like Ebola and HIV in pregnant individuals, creating reliable data while safeguarding participants and their babies. Yet, challenges related to logistics, regulations, and ethics persist.

Wall indicates that while there isn’t evidence showing that recent policies have reduced the participation of pregnant individuals in trials, there is concern that growing anti-pharmaceutical sentiment might deter studies on medications during pregnancy, further delaying efforts to address evidence gaps.

Denise Astill, who took sodium valproate during her pregnancy before clear warnings were issued, emphasizes that true progress in this area hinges on equity. Her twin daughters face various health issues as a result. This experience motivated Astill to create a charity in New Zealand focusing on providing guidance regarding anti-seizure medications during pregnancy. She argues that pregnant individuals should have access to evidence-based medical care just like anyone else, highlighting the limitations of a health system primarily based on male studies.

The Legacy of Thalidomide

The caution surrounding medical research during pregnancy can be traced back to a major medical disaster involving thalidomide in the late 1950s. Marketed as a morning-sickness remedy in 46 countries, this drug had not been tested on pregnant people. Soon after its usage, a rise in births of babies with serious limb deformities became evident.

By the early 1960s, it was confirmed that thalidomide caused congenital disorders in over 10,000 children, leading to the drug’s withdrawal. This event prompted stricter drug regulations, inadvertently excluding pregnant individuals from clinical trials.

The Declaration of Helsinki in 1964 categorized pregnant individuals as ‘vulnerable,’ similar to those unable to provide informed consent. In 1977, the U.S. drug regulator prohibited both pregnant individuals and women of childbearing age from participating in trials. Although some changes began in the late 1980s and early 1990s requiring inclusion in research, pregnant individuals continued to be marginalized due to their classification as vulnerable.

In the last ten years, some restrictions have relaxed. The World Health Organization now suggests considering pregnant people as ‘complex’ rather than simply ‘vulnerable’ and encourages their inclusion in trials when feasible. However, progress has been slow, with under 1% of drug trials in the U.S. from 2008 to 2023 specifying the inclusion of pregnant participants, and a mere 0.4% in Europe.

Creating evidence takes time. With COVID-19 vaccines, rapid vaccination led to quick data collection. By the end of the pandemic, most nations recommended vaccination during pregnancy. Still, a review of drugs approved by the U.S. FDA found that it generally takes, on average, 27 years to gather sufficient evidence on a drug’s safety in pregnancy post-approval.

This gap poses a challenge for healthcare providers and pregnant individuals: either resort to medications with unknown risks or forgo treatment altogether. “Sometimes, asking your doctor is helpful because they have access to much information,” says Alyssa Bilinski, a statistician at Brown University. “But this advice can’t replace the long-standing underinvestment in research.”

Bilinski’s research suggests that the exclusion of pregnant individuals from randomized trials can have dire consequences. A previous study indicated that testing thalidomide with pregnant participants could have prevented nearly 8,000 congenital disorders, highlighting the potential harm caused by excluding this group from research.

The same analysis indicated that pregnant individuals’ exclusion from early COVID-19 vaccine trials might have resulted in additional maternal deaths and stillbirths in the U.S. Had trial data been available, it could have led to a reduction of around 20% in such unfortunate outcomes between March and November 2021.

Many believe that risks arise only from taking medications, but neglecting treatment can be equally harmful, exposing both the pregnant individual and their baby to serious health threats. “What occurs in the absence of a trial can often result in the worst-case scenario,” Bilinski remarks.

Overcoming Obstacles

Some barriers to involving pregnant individuals in clinical trials are genuine, while others are misconceptions, explains Anna David, an obstetrician and maternal-fetal medicine expert at University College London. Contrary to the myth that pregnant individuals won’t sign up for trials, David finds that many are willing to participate when they are fully informed and can provide consent.

Another misconception is the belief that fetal health cannot be monitored during trials, which is inaccurate. “As a fetal medicine specialist, I determine this all the time,” David asserts.

To facilitate better tracking of risks in trials involving pregnant individuals, David’s team has created standardized definitions and grading systems for potential issues impacting both mother and fetus. These criteria, developed in 2021, have since been integrated into trials and recognized in numerous publications.

Nevertheless, pharmaceutical companies frequently hesitate to include pregnant individuals in studies. Concerns over negative publicity from adverse outcomes contribute to this reluctance. “Imagine the headlines for a new drug with poor outcomes,” reflects David.

Insurance challenges also hinder researchers, as insurers often assess risks by relying on data from past trials, which is scarce for pregnant subjects. The lack of this data can lead insurers to deny coverage or impose steep premiums.

Even with insurance, conducting clinical trials during pregnancy tends to be more expensive due to the necessity for specialized resources and expertise. Estimates suggest that developing a medication specifically for pregnant individuals might incur an additional cost of approximately $5.7 million compared to drugs used in other fields, primarily due to safety and efficacy studies.