Why Is Good Medical Advice for Pregnant Women So Hard to Find?

A recent warning about the pain reliever acetaminophen is a reminder that health risks in pregnancy remain maddeningly, dangerously understudied.,

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If you have spent the pandemic calculating the potential costs and benefits of every action you might take — whether to travel, to work, to see family, to seek medical care — while fearing that a misjudgment will result in catastrophe, you have some idea of what it can feel like to be pregnant in the 21st century. Women have been warned that everything from fish to frozen yogurt, alcohol, coffee, X-rays and airplane flights can harm an unborn child. In most such cases, the reproductive risks “tend to be fairly small, if they exist at all,” says Anne Drapkin Lyerly, a professor at the University of North Carolina’s Center for Bioethics. But just the possibility of a negative outcome, however unlikely, can obscure what might be the greater benefits of the action or substance in question.

The challenge in weighing risks while pregnant is especially difficult when it comes to medications — “There’s a lot of uncertainty and fear,” Lyerly says. But women cannot forgo treatment for conditions like diabetes, depression or high blood pressure the way they can give up unpasteurized cheese.

Last month, Nature Reviews Endocrinology published a statement raising concerns about fetal exposure to an over-the-counter medication that 65 to 70 percent of pregnant women in the United States report having taken: acetaminophen, a pain reliever and fever reducer commonly sold as Tylenol. Left untreated, fever during pregnancy has been linked to an increased risk of a child having neural-tube defects and cardiovascular disorders later in life. In adults, severe and ongoing pain can lead to depression, anxiety and high blood pressure, all of which can also negatively impact fetal development. There are compelling reasons to treat these conditions.

But while nonpregnant adults have multiple options for combating fever and pain, for pregnant women, acetaminophen — also an ingredient in hundreds of other cold, flu, allergy and sleep medications — is considered the safest choice. The Food and Drug Administration has so far found no conclusive evidence of risk during pregnancy when used as directed. And the agency warns against a common alternative: nonsteroidal anti-inflammatory drugs, which include aspirin, ibuprofen and naproxen (sold as Aleve). In rare cases when used in the second half of a pregnancy, they can lead to fetal kidney problems and low amniotic fluid levels.

Despite the clear need for acetaminophen to be available during pregnancy, the 13 authors of the Nature Reviews statement (which was signed by an additional 78 scientists) argue that raising awareness about its potential negative effects could have public health benefits. They considered evidence from observational and experimental studies and found an association between fetal exposure to the drug and neurodevelopmental disorders (including autism and A.D.H.D.) and reproductive and urogenital disorders (including early puberty and decreased fertility). In randomized controlled trials in animals, acetaminophen appeared to cause similar outcomes. The drug can disrupt the endocrine system, potentially affecting the activity of hormones that help regulate fetal development.

But the associated risk appeared to be small. “One reason this has been overlooked is because the risk is not that great for an individual, and you need to have really good studies to find an association,” says David M. Kristensen, an associate professor at the Danish Headache Center at the University of Copenhagen and one of the statement’s authors. In studies for which women reported the drugs they took, the strongest links were among those who said they used acetaminophen for more than 14 days. (The authors noted that the existing studies included only cisgender women.) Given that so many pregnant women take acetaminophen, even a slight reduction in individual consumption could theoretically result in an overall decrease in the associated disorders.

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Credit…Ori Toor

Crucially, however, it is not possible to say for certain whether acetaminophen caused those disorders in people. (Neurodevelopmental disorders are believed to be the result of multiple factors.) It could be that women who took the drug were more likely to have faced other potential risk factors, like stress or illness. As the American College of Obstetricians and Gynecologists observed in a written response to the paper, there is still “no clear evidence that proves a direct relationship between the prudent use of acetaminophen during any trimester and fetal developmental issues.” Kristensen believes we will never get that clear evidence. That’s because proving that acetaminophen causes the associated disorders, and at what dose, traditionally requires a randomized controlled trial, in which the drug is given to some pregnant women and a placebo to others. Because there is already some evidence that acetaminophen could be harmful, that would be considered by some to be unethical.

And yet it’s in widespread use. In fact, there are hundreds of medications potentially being taken by pregnant women about which little is known, says Xiaobin Wang, a pediatrician and director of the Center on the Early Life Origins of Disease at Johns Hopkins Bloomberg School of Public Health. “There are so many questions” about these drugs and pregnancy, she says, “and so little data to provide definite answers.”

In part this is because pregnant women have long been excluded from clinical trials for drugs that might be beneficial. A 2014 review published in Frontiers in Pediatrics found that from the late 1960s through August 2013, just 1.3 percent of clinical trials focusing on how drugs move through the body included pregnant participants. The consequences of this lack of research have been that those who are pregnant must take such medications anyway, but without any data to say what dose is safest and most likely to work — a significant deficit, given that pregnancy causes the body to metabolize drugs differently. “If you don’t do studies in pregnant and lactating women, rather than protecting pregnant women, you’re going to provide care without any evidence to guide it,” says Catherine Y. Spong, chief of the division of maternal fetal medicine at the University of Texas Southwestern Medical Center. That may include relying on older medications with longer track records for which potential risks appear small — like acetaminophen — when newer ones could be safer and more effective.

“It’s not that we cannot do it,” Spong adds. There are, after all, clear protocols for including pregnant participants in medical research. For example, they can be enrolled in clinical trials of new treatments if researchers do preliminary reproductive toxicology studies in animals. But for medications already in use, it has been harder to find the funding needed to study them (though there is legislation that provides financing and incentives for research to be done on children’s medicines). Simply put, those who are pregnant have been left without the same evidence-based treatment options available to other adults.

In the absence of better guidance or options, Kristensen and his colleagues say that women who need acetaminophen should keep taking it in consultation with a physician. (In fact, asking a doctor before taking any medication is already standard advice for pregnant women.) Their goal in publicizing their findings is to reach pregnant people, who, they say, surveys have shown may be taking the drug without being aware of its potential risk, or who are using it in an ongoing effort to manage conditions — like back pain or migraine — for which it is not very effective. In those cases, popping a few Tylenol and toughing it out over an extended period might come with more risk than previously realized while not necessarily resolving the user’s pain. The statement’s authors also hope to spur more research, and to persuade regulatory agencies, including the F.D.A., to review the existing literature.

But the question remains how best to respond to risks during pregnancy that — frustratingly and frighteningly — are complex and hard to quantify. “It may be we never really have an answer,” says Sarah Richardson, a professor of the history of science at Harvard. “If we can never know, should we act on it?” In this case, she argues no: “If this is the bar for issuing precautionary action, we might find ourselves in a scenario where everything and anything is dangerous for pregnant women.” Kristensen disagrees: “I would rather be informed of potential risk than live in lack of knowledge.” But, he adds, “This is not a black-and-white discussion.”

Kim Tingley is a contributing writer for the magazine.

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