Questions remain about the safety of most medications during pregnancy
People generally take medication to address potentially harmful health conditions. Because all medications present some risks, a patient and their healthcare provider must decide together whether the potential benefits outweigh the risks. This calculation often becomes more complicated when a patient becomes pregnant. While leaving a condition untreated can harm both the parent and the fetus, treating the condition can present some risks to the fetus itself.
Because most people who decide to have a baby want to do what is best for the developing fetus, they initially might lose sight of the reality that protecting their own health is one of the most important things they can do for a healthy pregnancy and baby. Healthcare providers must help them balance the risks and benefits of using medication for themselves and their developing fetus. Even though more than 90 percent of women took at least one over-the-counter or prescription medication during pregnancy, 60 to 90 percent of prescription medications lack sufficient safety information for use during pregnancy.
Before a medication is approved for use in the general population, it must undergo clinical trials to assess its safety; however, these trials typically exclude people who are pregnant or planning to become pregnant unless the medication is designed to treat a pregnancy-related condition. Many also require women to use a highly effective means of birth control for the duration of the trial to prevent unplanned pregnancy. Moreover, if a clinical trial participant becomes pregnant, protocol typically dictates that they must discontinue treatment and be monitored to assess pregnancy outcomes. Clinical trials are leery of including pregnant individuals for a number of reasons, with logistics and risk being the main challenges.
Understanding why there is so little information about medication use during pregnancy requires a basic understanding of drug development. Medications are developed and tested on animals before progressing to human trials. However, because of increased costs, logistical challenges, and the concern that females’ hormonal fluctuations could complicate analysis, studies would often use male cells and animals exclusively. Excluding female subjects in early drug development is one reason that information about medication safety during pregnancy is lacking. It was not until 2016, when the National Institutes of Health mandated that all grant applications include plans to include female and male animals or cells in studies unless there was a legitimate reason not to do so, that early drug research began to routinely use female animals and cells.
Similarly, most clinical trials enrolled male participants only until 1993, when the Food and Drug Administration (FDA) and Congress reversed a 1977 guideline that excluded women of childbearing age from participating in early stage clinical trials. The FDA implemented this guideline after the “thalidomide scandal” of the 1960s. Thalidomide is a medication that was used abroad (but never approved in the United States) to treat many conditions, including morning sickness. While the drug proved safe when tested on animals, if taken during pregnancy, it caused severe birth defects and, in many cases, infant death. The magnitude of thalidomide’s harm (more than 10,000 babies were affected, of which about 50 percent died) sparked many changes to drug-approval processes and clinical testing worldwide. Many of these changes were positive, but a repeat of the thalidomide scandal is still possible—particularly with newly approved medications, as healthcare providers typically have limited real-world evidence to help determine whether a medication’s risks outweigh its benefits for both parent and fetus.
Given that cost, logistics, and risk to the fetus present challenges to including pregnant people in clinical trials, observational research conducted after a drug’s approval is the primary way to gather safety information for pregnant people. This type of research has the advantage of being able to assess a larger group of people, which makes it more likely to uncover rare side effects from medications. It does not involve intentionally exposing participants to a potentially harmful substance, which simplifies ethical considerations; however, an important disadvantage is that it is nearly impossible to prove direct causation via observational research only. Another disadvantage is that gathering this information takes time and often requires the medication to be prescribed to pregnant individuals “off-label” (for unapproved use), leaving prescribers to make case-by-case recommendations. Still, observational data is valuable in determining medication safety.
After a medication receives FDA approval, additional required or optional safety monitoring is sometimes established, which often involves collecting observational data. This adverse-event reporting through the FDA is one way medications are monitored for safety after initial approval. The reports are submitted to the FDA by manufacturers and by a program called MedWatch that collects information from consumers and providers. Another safety-monitoring tool is the FDA’s Sentinel Initiative, which captures data from patient encounters with the healthcare system to help regulators spot potential problems not gathered in clinical trial data.
Some studies set up patient registries specifically for people taking medication during pregnancy. In some cases, the FDA requires companies to establish these registries as a condition of approval. Patient participation is voluntary, which often means that enrollment (especially soon after a medication is approved for use) can be low, decreasing the registry’s ability to detect potentially harmful medication effects. Another source of safety data is a study funded by the Centers for Disease Control and Prevention that collected information about risk factors for birth defects from more than 40,000 pregnancies. This study has contributed to guidelines and recommendations for medication use during pregnancy.
It is incumbent upon regulatory and healthcare organizations to advance existing knowledge on the safety of medication use during pregnancy. While excluding pregnant individuals from clinical trials avoids short-term ethical and logistical challenges for regulators and trial sponsors, it leaves patients and providers responsible for absorbing the risk of choosing to use an untested product while observational data is collected. Until a feasible solution is found for including pregnant individuals in clinical trials, patients and providers must do their best to balance risks to parent and fetus on a case-by-case basis.
The nebulous nature of existing information highlights the importance of prenatal care, which allows shared decision-making between patient and provider about medication use based on the best information available. Pregnancy is often a time of great excitement—and sometimes anxiety—but open communication between patients and providers helps ensure that questions about medication safety do not affect the experience.