Acetaminophen use in pregnancy not linked to neurodevelopmental disorders, large study finds

By Mira Cheng, CNN

(CNN) — Using acetaminophen, the active ingredient in Tylenol, during pregnancy was not associated with increased risk of autism, ADHD or intellectual disability in children, a new study found.

The study, published in the journal JAMA on Tuesday, analyzed the prenatal and medical records of about 2.5 million children born in Sweden between 1995 and 2019.

A statistical model comparing children exposed to acetaminophen during pregnancy with those not exposed found that there was a marginally increased risk of autism, ADHD and intellectual disability in the exposed group. However, a sibling analysis that looked at the exposure and outcome of full sibling pairs — siblings with the same biological parents —  found that there was no evidence of increased risk of autism, ADHD or intellectual disability associated with acetaminophen use during pregnancy, according to the study led by scientists from the Karolinska Institute in Sweden and Drexel University.

Sibling analyses are powerful because siblings share genetic and environmental factors, and this eliminates some of the confounding variables that can skew results in clinical trials, according to the study.

“Matched sibling control studies better control for environmental factors that are unknown to the investigators,” Dr. Eric Brenner, an assistant professor of pediatrics at Duke University who was not involved in the research, said in an email to CNN. “Sibling controls will most likely grow up in the same home, have similar diets, and will be exposed to similar environments which allows investigators to better control for environmental factors.”

Brenner said that the large number of participants and the sibling analysis are both strengths of the study.

“This is a very extensive and well-designed study that found no association between acetaminophen use and neurodevelopmental impairment, including autism and ADHD,” he said. “While any medication should always be used judiciously and in consultation with an obstetrician, it appears that acetaminophen is safe.”

These new findings refute recent research papers and statements that suggest that there is an increased risk of autism, ADHD and intellectual disability associated with acetaminophen use during pregnancy.

While the US Food and Drug Administration and the European Medicines Agency consider acetaminophen to pose minimal risk during pregnancy, a 2021 statement by an international group of scientists and doctors called for precautionary action and recommended that pregnant individuals “forgo [acetaminophen] unless its use is medically indicated.” And a spate of research papers linked acetaminophen use during pregnancy to increased risk of ADHD and other neurodevelopmental disorders.

The authors of the new study wrote that “this suggests that associations observed in other models may have been attributable to confounding.”

Confounding is when an external factor influences both the exposure and the outcome and creates a false association between the two. For example, the study found that parents who have neurodevelopmental disorders — which have strong heritability — are also more likely to use pain medications, like acetaminophen, during pregnancy. This relationship might make it seem like children who are exposed to acetaminophen during pregnancy are more likely to develop neurodevelopmental disorders, when, in fact, their increased risk is due to genetics, according to the study.

The study found significant differences between birthing parents with higher acetaminophen use and those with lower or no use. Acetaminophen exposure was more common among children born to parents in a lower socioeconomic class, with a higher early pregnancy body mass index, those who smoked during pregnancy and those with diagnoses of psychiatric disorders or neurodevelopmental conditions.

“Results suggested that there was not one single ‘smoking gun’ confounder, but rather that multiple birthing parents’ health and sociodemographic characteristics each explained at least part of the apparent association,” the researchers wrote.

Interestingly, the study also found that other painkillers, such as aspirin, other NSAIDs and opioids, were not associated with increased risk of neurodevelopmental disorders in sibling analyses; each type of painkiller had previously been associated with birth defects. Aspirin use, in particular, was associated with a decreased risk of neurodevelopmental disorders in this study; however, this is an early finding, and more investigation is needed to understand this result, Brenner said.

“At this time, aspirin use is not routinely recommended in pregnancy, and I would urge pregnant mothers to discuss its use with their obstetricians,” he said.

Brenner said that fevers are common and occur in over 10% of pregnant individuals. Most of the time there are no effects on fetal development, he said, but fevers in the first trimester have an increased association with serious congenital defects such as cleft palate and heart defects.

Acetaminophen is one of the most commonly used and well-studied medications in pregnancy and is considered safe to use to reduce fever and pain judiciously, Brenner said.

The FDA recommends against using NSAIDs, including aspirin and ibuprofen, in the third trimester of pregnancy because these drugs may cause a blood vessel in the fetus to close prematurely.

Dr. Yalda Afshar, an assistant professor in-residence of obstetrics and gynecology at the David Geffen School of Medicine at UCLA who was not involved in the new research, said in an email to CNN that she recommends that people consult with a health care professional about the use or discontinuance of any prescription and over-the-counter medication during pregnancy.

“Hopefully this study will provide reassurance to pregnant people who need to take acetaminophen to optimize their health in any way,” she said.

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