New research cautions about possible risks of acetaminophen use during pregnancy

Nearly 100 doctors and scientists issued a consensus statement Thursday warning of possible links between the use of acetaminophen during pregnancy and developmental problems in children, including neurological and reproductive issues that start in the womb.

In a paper published by Nature Reviews Endocrinology, the authors reviewed the medical literature going back 25 years to make a set of recommendations. The group is calling on clinicians and regulatory agencies to change their guidelines for the use of acetaminophen during pregnancy while more research is conducted to study the full range of effects the drug could have on fetal development and children.

Acetaminophen, or APAP, is a pain-relieving and fever-reducing ingredient used in hundreds of medications, including prescription drugs as well as over-the-counter formulations like Tylenol, DayQuil, and Benadryl. It is estimated that over half of all pregnant women in the world use APAP.

While the group supports the current global recommendation that already advises taking as little APAP as possible for as short a time as possible during pregnancy, the consensus statement is “asking for more,” said Shanna Swan, one of the lead authors and a professor at the Icahn School of Medicine at Mount Sinai. Patients, physicians, and regulators should be fully informed of new data that suggests “pretty significant risk” before casually using APAP, she said.

The group asked, in its list of recommendations, for OB-GYN associations to review the research and update their guidelines. But Christopher Zahn, vice president of practice activities for the American College of Obstetricians and Gynecologists, said in a statement that he did not see a basis for altering what clinicians already do. He said the new paper and past studies “show no clear evidence that proves a direct relationship between the prudent use of acetaminophen during any trimester and fetal developmental issues.”

Zahn added, “The authors are not recommending anything counter to what is already done by obstetrician-gynecologists when prescribing acetaminophen for a given clinical condition. Physicians should not change clinical practice until definitive prospective research is done and, most importantly, patients should not be frightened away from the many benefits of acetaminophen. However, as always, any medication taken during pregnancy should be used only as needed, in moderation, and after the pregnant patient has consulted with their doctor.”

The research was led by Swan and Ann Bauer, a postdoctoral fellow at the University of Massachusetts Lowell, working under the guidance of senior author David M. Kristensen, a professor at the University of Copenhagen. They reviewed experimental and epidemiological papers that were published on the subject from 1995 through October 2020, looking only at studies that analyzed APAP as an independent exposure.

The research the authors reviewed did not include data for pregnant transgender men, nonbinary people, or intersex people.

The authors used findings from rodent models and laboratory and human studies — most of which suggested that, while risk from one-time APAP use during pregnancy “is relatively modest,” the risk increases with repeated use and higher dosages, they wrote.

The consensus statement is supported by an international group of 91 scientists, public health experts, and clinicians, including doctors specializing in neurology, obstetrics, gynecology, and pediatrics, and scientists who study toxicology, endocrinology, reproductive medicine, and neurodevelopment.

“Why is this consensus coming out now?” Swan said. “Why is it supported by so many people now and not in the past? And I think it would be because of what we see: As time progresses and studies get better and measurement gets more precise, which is what we’re seeing, we see a stronger effect. If it had been in the reverse – if more precise studies made the effects go away – then we wouldn’t be here. But the fact that as time progresses, we see stronger and stronger evidence suggests that we’ve only been underestimating risk.”

Researchers identified three key areas of fetal development that the studies suggest might be affected by prenatal exposure to APAP: neurological, reproductive, and urogenital. APAP is an endocrine disruptor, meaning it can interfere with the distribution of bodily chemicals and hormones that are critical for a fetus’s healthy development.

The exact mechanism by which APAP might block these key biological processes is not yet known, the authors say. However, studies suggested that those in utero effects could disrupt the proper formation of reproductive tracts and organs, affecting how well they work later in life. Neurodevelopment problems also showed up in the data. That association, between a commonly used drug and widespread health issues like infertility and ADHD, left Swan and Kristensen “concerned.”

Even when studies tried to control for confounding factors, such as genetics and socioeconomic status, which could influence the relationship between APAP use and developmental problems, “the associations remained robust,” Bauer said. “So it seems, to me, that it’s quite consistent, what they’ve found.”

Those findings led to the main conclusion of the paper: Until the risks are fully known and explored, “we should reduce our use of acetaminophen when possible throughout the entire pregnancy,” Bauer said.

It’s not yet known how much APAP is too much, and that’s because studies on humans often can’t pinpoint exactly how much APAP pregnant people use, and how often or when in pregnancy they use it. Studies have shown that pregnant patients often fail to report the drug in their list of medications unless specifically asked by a clinician about name-brand, APAP-containing medicines.

To account for the gap between actual and reported use of APAP during pregnancy, the authors also analyzed studies that tested pregnant patients for biomarkers. With those biological measurements, the links between APAP use and developmental issues became stronger — showing a “twofold increase of risk” for attention deficit hyperactivity disorder (ADHD) and a threefold increased risk of autism, Bauer said in a news conference.

To Kristensen, the inaccuracy of a lot of self-reported use data indicates that some pregnant people “do not consider APAP as a true medication” with side effects. That disconnect could be due to the drug’s ubiquity. Unlike in other countries, where acetaminophen products are only available in pharmacies, products containing APAP are available in the United States at gas stations, grocery stores, and even vending machines.

Medications such as Tylenol have long been considered the safest way to treat fever and pain in infants and children, and are still one of the only types of drugs that haven’t been flagged by the Food and Drug Administration as being risky during pregnancy.

In 2020, the agency warned of risks associated with the use of non-steroidal anti-inflammatory medications, such as ibuprofen, in the second half of pregnancy. With those drugs ruled out, “there was nothing left” for patients to take when dealing with fever and pain during the second half of pregnancy, Swan said. The FDA previously reviewed some data on issues related to APAP use during pregnancy, but there have been more than two dozen other studies on the subject since then – convincing ones, according to Bauer.

Among other recommendations, the consensus statement asks the FDA to update its recommendations in a 2015 drug safety communication “based on evaluation of all available scientific evidence, including both epidemiological and experimental evidence.”

In a statement, an FDA spokesperson said the 2015 recommendations did review possible risks of acetaminophen use during pregnancy.

“The benefits and risks of acetaminophen use during pregnancy should be carefully considered,” the spokesperson said. “Pregnant women should always consult with their health care professional before taking any prescription or nonprescription medicine. The FDA continues to monitor and evaluate the use of acetaminophen during pregnancy and will update the public as new safety information becomes available.”