US regulators are seeking to expand the knowledge base about potential side effects of medicines when taken during pregnancy because clinicians and their patients have long been concerned about the lack of information in this field.

Speaking on May 8 at a workshop held by the FDA, Kavita Shah Arora, MD, MBE, MS, recalled a recent conversation with a patient who was weighing whether to take a certain medication while pregnant.

The patient was appalled by the paltry amount of information available for her in making this decision, said Arora, who spoke at the FDA workshop as the representative of the American College of Obstetricians and Gynecologists.

Arora quoted her patient as saying, “so I have to make a decision based on one study done 60 years ago on a rat, and probably a male rat,” drawing knowing laughter from the attendees of the FDA workshop.

“She’s not that far off,” Arora said.

Drugmakers routinely use pregnancy and lactation as reasons to exclude patients from clinical trials, seeking to protect fetuses and children from ill effects of experimental drugs. As a result of the lack of data from clinical testing, there is great dependence on postmarketing data to track potential side effects of medications when used during pregnancy and lactation.

FDA officials have for many years wrestled with approaches for gathering information about possible effects of medicines taken during pregnancy. In 2002, the FDA published a guidance document to help companies as they sought to track the outcomes of pregnancies exposed to specific medical products. This work is done through enrolling patients in registries.

On May 8, in addition to holding a public workshop, the FDA unveiled the final version of a new guidance document, titled “Postapproval Pregnancy Safety Studies.”

This new guidance document also addresses the operations of registries to study how approved medicines may affect women and children. At the FDA workshop, Arora suggested referring to these as “pregnancy exposure registries” rather than using the shorthand of pregnancy registries.

“Especially in our current political times, I worry about the implied goal of knowing who and when everyone in this country is pregnant, rather than the goal of understanding the prevalence and impact of exposures during pregnancy,” Arora said.

Arora pressed for reconsideration of pregnancy as an automatic exclusion from clinical trials. She asked that officials at the FDA and the National Institutes of Health as well as members of institutional review boards to look for paths to open trials, where possible, to those who are pregnant or lactating.

“This change in culture is imperative at every level of the research infrastructure,” said Arora, who is a professor and the division director for general obstetrics, gynecology, and midwifery at the University of North Carolina at Chapel Hill.

In the new guidance document, the FDA noted the benefit of including more pregnant participants in clinical research.

“Ideally, safety information on drugs used during pregnancy should be obtained in the premarketing setting with evidence from well-designed randomized clinical trials, as appropriate,” the agency said.

But the FDA guidance mostly offered detailed suggestions on other approaches to studying the effects of medicines taken during pregnancy and lactation, such as registries and case reports. The guidance also suggests other sources of data, including medical claims data and electronic health records.

Real-World Challenges

There were about 3.6 million births in the US last year, according to the CDC. Research indicates prescription drug use is common among those expecting, with one study finding that 97% of participants took at least one medication during pregnancy.

In the new guidance document, the FDA notes that chronic conditions such as diabetes, seizure disorders, or asthma require continued treatment during pregnancy.

At the FDA workshop, several participants mentioned the particular challenges faced by women with systemic lupus erythematosus (SLE) when they become pregnant.

The condition itself can raise the risk for certain complications during pregnancy for both the patient and the fetus. And people with SLE may face tough choices about continuing medications while expecting without definitive information about risk.

For example, a 2023 paper in the Annals of the Rheumatic Diseases described as the “largest descriptive summary of birth defects and pregnancy losses” among patients with SLE who took belimumab and their children fell short on definitive conclusions.

Data sources for this paper included participants in belimumab clinical trials who became pregnant, the Belimumab Pregnancy Registry, and postmarketing reports of belimumab-exposed pregnant women with SLE.

Yet the researchers could not offer much in terms of solid evidence for people taking belimumab to weigh if considering becoming pregnant.

“Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use,” wrote the authors of the 2023 paper.

Among the authors of that paper were Keele Wurst, PhD, MS, RPh, head of immunology and emerging epidemiology at GSK and co-chair of the giant drugmaker’s Pregnancy Outcomes Advisory Panel.

Wurst spoke on the first day, May 7, of the FDA workshop. She noted that hurdles in gathering data on pregnancy outcomes and SLE drugs can include questions about whether a rheumatologist or an obstetrician would enroll a patient in a registry.

There have been increased efforts in recent years to reach out directly to patients and recruit them to join pregnancy-exposure registry studies. The medication guide for belimumab includes information on how to contact MotherToBaby, a research effort of the nonprofit Organization of Teratology Information Specialists. The belimumab study is one of many being run through the MotherToBaby program, which is coordinated by the Center for Better Beginnings at UC San Diego (UCSD).

At the FDA workshop on May 8, Christina Chambers, PhD, MPH, principal investigator for the MotherToBaby program, urged more coordination of research on the effects of medication during pregnancy and more reliable funding for this work.

About 200 different registries have been created to study the effects of medication taken during pregnancy and lactation, with many of them focused on a single drug. This fragmented approach leaves patients and clinicians with a daunting task in even finding a registry, she said.

“Someone has to search. Someone has to take the effort and time to try to find one,” said Chambers, who also is a professor of pediatrics and chief of the Division of Environmental Science and Health at UCSD.

A shift toward a more universal approach, akin to the MotherToBaby program, would make it easier for patients and clinicians to find studies, she said.

A step toward this would be to consolidate, rather than duplicate, existing resources that are supporting these registries, she said. There also could be pooling of industry resources, moving toward a public-private partnership model.

Another way to fund this research might be to seek changes in the next version of the Prescription Drug User Fee Act (PDUFA), Chambers said.

This law, first passed in 1992, created a dedicated source of revenue to fund the review of applications from drugmakers. This approach proved popular. Congress has decided to put the PDUFA law on 5-year cycles. This creates a virtually must-pass law that can carry with it many changes to the FDA policy beyond setting the user fees.

The current law, PDUFA VII, largely sunsets at the end of fiscal 2027, or September 30, 2027. That’s why the FDA last year began a series of discussions with representatives of pharmaceutical companies and advocacy groups and researchers about what changes to make in PDUFA VIII.

It might be late in the process to try to add into PDUFA VIII a mechanism for new funding for pregnancy-exposures, Chambers said. Still, it is members of Congress who next year will ultimately decide what the bill includes.

“To me, this makes complete sense that a small portion of user fees could be allocated to support a universal pregnancy registry,” Chambers said.

Chambers reported receiving research funding from Amgen, AstraZeneca, GSK, Janssen, Pfizer, Regeneron, Hoffman La-Roche-Genentech, Sanofi-Aventis, Takeda, UCB Pharma USA, Leo Pharma, Sun Pharma, Gilead, Novartis, Bristol Myers Squibb, Celgene, Novartis, CSL, Johnson & Johnson, Eli Lilly, and The Gerber Foundation.  Arora had no relevant financial disclosures.

Kerry Dooley Young is a freelance journalist based in Washington, DC. She has covered medical research and healthcare policy for more than 20 years.