One of the painkillers considered safest for women to take during pregnancy -- acetaminophen (Tylenol) -- has recently come under scrutiny for its potential link to adverse fetal outcomes.
Earlier this month, a group of 91 scientists, clinicians, and public health professionals signed a consensus statement cautioning against the use of acetaminophen in pregnancy.
The statement, published by Ann Bauer, ScD, of the University of Massachusetts in Lowell, and colleagues in , warned of potential links to adverse fetal development outcomes, called for further investigation, and encouraged extra precautions prior to use in pregnancy.
But many say this "consensus" is no real consensus at all, and may be sending the wrong message to patients who need to take the medication. As acetaminophen is one of the only medications considered safe to treat pain and fever in pregnant patients, experts have questioned the limitations of the evidence included in the review, as well as what a lack of other medication options means for those who need it.
"I don't think we should actually be sending the message to pregnant individuals that, 'well, there's no safe pain medicine that you can take, so you should just have pain,'" said Katie Gray, MD, PhD, a maternal-fetal medicine specialist at Brigham and Women's Hospital in Boston. "I don't think that's appropriate care for patients.
Acetaminophen is an active ingredient in more than 600 medications and is widely used among pregnant patients to treat pain and fever, according to Bauer's group. It's estimated to be used by 65% of pregnant people in the U.S., and half of the pregnant population worldwide.
The medication, which has the chemical name paracetamol (N-acetyl-p-aminophenol; APAP), is also an endocrine disruptor, Bauer and colleagues argued, which could increase the risks for neurodevelopmental, urogenital, and reproductive disorders when used in pregnancy.
Observational studies and animal experiments suggested that acetaminophen exposure in utero was associated with urogenital and reproductive tract abnormalities among male infants, and early puberty among females. It was also associated with neurodevelopmental disorders -- such as attention deficit-hyperactivity disorder, autism spectrum disorder, and decreased IQ.
"This APAP Consensus Statement is a call to prioritize research initiatives and to provide evidence-based medical guidance for APAP use by pregnant women, with the goal of creating awareness so women can make informed decisions that will lead to minimizing APAP exposure," Bauer's group wrote. "We here recognize our professional and social responsibility to take this action, even in the face of uncertainty, in light of the serious consequences of inaction."
While the authors noted the limitations of the epidemiological research in their review, they recommended that pregnant women forgo acetaminophen use if not medically necessary, consult with a physician or pharmacist before using the medication on a long-term basis, and minimize their risk by using the lowest dose for the shortest duration possible.
But clinicians say that these recommendations will not alter the way they treat their pregnant patients for fever or pain -- two conditions that may pose their own dangers to a baby in utero.
"I think we should obviously continue to gather data about the safety of Tylenol and all medications in pregnancy," Gray said. But if pregnant individuals need treatment, she said that "we shouldn't be withholding Tylenol based on what we know."
Gray added that while the article addresses concerns about potential associations between acetaminophen use in pregnancy and fetal disorders, she does not believe "that it adequately acknowledges how few options pregnant patients have to treat pain."
There's no safe alternative to treat pain and fever during pregnancy. Non-steroidal anti-inflammatory drugs (NSAIDs) -- such as aspirin or ibuprofen -- and opioids are known to pose risks to the fetus in both the early and late stages of pregnancy.
Last year, the FDA warned against NSAID use after 20 weeks' gestation, citing evidence that it might cause fetal kidney issues and low amniotic fluids. Additionally, the FDA said that use of the medications was linked to fetal heart problems after 30 weeks of pregnancy.
Researchers have also warned against NSAID and opioid use as early as the first trimester. In 2017, CDC researchers found heightened risks of among babies whose mothers self-reported NSAID or opioid use in the first trimester, compared to those who used acetaminophen.
Given few treatment alternatives, ob/gyns told 鶹ý that the data in this review -- which is largely retrospective -- should not significantly alter clinical practice. In observational studies, it is difficult to attribute neurological or reproductive disorders among children to one single cause. Gray said it's nearly impossible to determine if a disorder might be caused by a medication, the medical indication for why a patient is taking a medication, or other common traits between a group of patients with a specific illness.
Additionally, many of the studies included in the review depended on self-reported data. Loralei Thornburg, MD, a maternal-fetal medicine specialist at the University of Rochester Medical Center in New York, said that the dependence on patients' recall of their medication use may have led to an under- or over-estimation of the associations between acetaminophen use and developmental disorders.
Many have recognized that further research is needed to compare safe medications in pregnancy. But until higher quality evidence is available, recommendations for pregnant patients with fever or pain should stay the same: administer at the lowest dose, and shortest duration possible. Medical societies for ob/gyns, including the (ACOG) and the (SMFM), have made statements continuing to encourage the safe administration of acetaminophen to patients who need it during pregnancy.
Kjersti Aagaard, MD, PhD, a maternal-fetal medicine specialist at the Baylor College of Medicine in Houston, said the authors of this review argue that judicious use of acetaminophen to relieve headaches and muscle aches among pregnant patients should be considered carefully until more research is available.
But while this precautionary statement does indeed aim to protect patients, more research is critical to understand the true cause of poor outcomes, Aagaard told 鶹ý in an email. The evidence does show that acetaminophen is associated with adverse fetal outcomes, but so are many environmental chemicals and pollutants -- as well as climate change.
"It would be a real mistake with real-life implications if we mistakenly associate any congenital disease or disorder to a commonly used medication with known benefits, if the true causal link lies elsewhere," she said.