By Brittany Wade

October 4, 2022 | Pregnant women have consistently been underrepresented in clinical trials. With studies posing significant risks to the mother and fetus, requiring extensive follow-up procedures for up to three years postpartum, and potentially jeopardizing market approvals, many pharmaceutical companies avoid this demographic almost entirely.  

As a result, healthcare providers frequently struggle to access data regarding drug safety during pregnancy, effectively crippling their ability to practice data-driven medicine in pursuit of the best possible outcomes.  

Additionally, medically complex pregnancies are on the rise as women wait longer to have children. Even under ideal circumstances, the chance of complications in labor is high. These conditions create a perfect storm where many pregnant patients are left without safe and effective treatment options, causing unnecessary maternal and fetal deaths.  

“Pregnant people make decisions in a vacuum of evidence,” Dr. Anna David, obstetrician and director of the University College London (UCL) Institute for Women's Health, tells Deborah Borfitz, Clinical Research News senior writer and host of the Scope of Things podcast. “Very often, their healthcare providers don’t know the evidence, so the women actually make the decision and take the risk that everyone else is ignoring. I think that has to stop.” 

The underrepresentation of pregnant patients in clinical research is a global issue. Various trial regulators recognize that excluding pregnant patients causes more harm than good. Four years ago, the U.S. Food and Drug Administration (FDA) issued a guidance document supporting the “judicious inclusion of pregnant women in clinical trials and careful attention to potential fetal risk,” asserting that increasing knowledge surrounding drug safety and efficacy in pregnant women is a “critical public health need.” 

Despite similar declarations from regulatory bodies like the European Medicines Agency (EMA) and Medicines and Healthcare products Regulatory Agency (MHRA), it was only until the late stages of the COVID-19 pandemic that these issues rose to the surface on a mass scale. 

“Essentially, most trials exclude pregnant women, and I think the COVID pandemic really brought it home,” says David. “Pregnant women with COVID-19 were less likely than other COVID-19 patients to receive effective treatments because of the lack of information available to clinicians and themselves about the impact on their child.” 

Ultimately, the pandemic highlighted what healthcare practitioners already knew: the exclusion of pregnant women in clinical research has far-reaching and potentially fatal ramifications. 

“We know that COVID had a disproportionately bad effect on pregnant women, particularly economically deprived communities [and] mixed ethnicity groups. We have to take this as an ethical problem. All people should be able to have access to the drugs that are right for them. If a pregnant person or woman needs a drug, we need to have the evidence to say that it’s safe for her and her baby.” 

Thankfully, the AIDS Clinical Trials Group (ACTG), one of the largest HIV research networks in the world, was one of the first to expand its COVID-19 and human monkeypox virus research to include pregnant women and children. 

The ACTG is not alone in this fight. Many organizations are emerging with a focus on inclusion and formulating an organized collection of evidenced-based data. 

For example, the Innovative Medicines Initiative launched a new project called ConcePTION in April 2019 to create a biomedical ecosystem chronicling evidence-based drug safety information during pregnancy and breastfeeding. ConcePTION offers an easily accessible online tool so that patients can make informed decisions before, during, and after pregnancy. 

Accelerating Innovation for Mothers (AIM) is a new campaign formed to understand pregnancy's specific challenges and examine target product profiles. The organization's website explains that only two drugs in history have been specifically designed for pregnant women. “Our medicine is the most advanced it's ever been, but not if you’re pregnant,” says AIM. 

Finally, the International Council for Harmonisation (ICH) formed a working group in May to develop recommendations that increase the inclusion of pregnant and breastfeeding women in trials. Eventually, ICH will commission a separate expert working group to convert those recommendations into actionable steps. 

Ideas and Solutions 

With many institutes, organizations, and working groups actively seeking to improve data access for pregnant patients, perhaps the state of maternal-fetal medicine is not as bleak as it seems. “There’s actually a lot of progress on this. Now we’re working on finding solutions,” says David. She is currently involved in a Birmingham Health Partners project called Healthy Mum, Healthy Baby, Healthy Future that removes the barriers preventing many pregnant women from entering clinical trials, including the obstacles involved in obtaining insurance.  

Solutions can also come from medically adjacent areas, such as pediatrics. In 2007, the EMA launched the Paediatric Investigation Plan, forcing pharmaceutical companies to determine whether their drugs were appropriate for children. This mandate improved the pipeline for children’s medicine, resulting in 260 new drugs or indications, and increased clinical trials for children by over 50 percent. David suggests a similar mandate—a Maternal Investigation Plan—could be established for pregnancy-related medications. 

One of the most helpful contributions to maternal and fetal medicine in recent years has been the development of the Maternal Fetal Adverse Event Terminology (MFAET)—which David helped create—as the first standardized vocabulary and grading system for maternal-fetal adverse events. MFAET offers a standardized framework to determine drug safety in the mother, fetus, and neonate based on dosage.  

The grading system includes 18 new terms evaluated on a scale of one to five, allowing researchers to compare drugs between trials. MFAET has already received endorsements from the FDA, EMA, and MHRA, and the response from the clinical research community has been overwhelmingly positive. 

Looking Ahead 

As more pregnant patients enter clinical trials, the opportunity for new lifesaving therapies also increases. For example, The EVERREST Consortium is creating the world’s first maternal gene therapy trial for pregnant women whose offspring are affected by fetal growth restriction (FGR). FGR occurs when a baby fails to reach a healthy weight during gestation, a condition that affects 1.46 million fetuses worldwide and contributes to approximately 50 percent of stillbirths. Currently, there is no viable cure for this condition. 

The trial would use gene therapy to potentially increase a growth factor (protein) in the mother to improve blood flow and encourage fetal growth. Coincidentally, MFAET will be used as the grading system to register any adverse events resulting from the trial. While the project has been in the works since 2014, David estimates another two to three years before completion. 

There are a few other notable studies. David mentions one to prevent hypertension in pregnancy and another to treat postpartum hemorrhage. UCL is looking to repurpose existing drugs by studying whether anti-transplant rejection medication can prevent stillbirths due to placental inflammation. They also create novel medicines for a fetal genetic disease called osteogenesis imperfecta or brittle bone disease. Last, a clinical trial in Europe and the United States uses intraamniotic protein therapy to treat a genetic fetal skin condition. 

With so many studies in the works and new therapies on the horizon, expectant mothers can be sure that, while incrementally, change is happening in the clinical research landscape. If physicians like Dr. David have anything to say about it, the future of maternal-fetal medicine is in excellent hands.