Pregnant women have long been assured that acetaminophen can treat their aches, pains and fevers without bringing harm to the babies they carry. Now researchers say they have found a strong link between prenatal use of the medication and cases of attention-deficit hyperactivity disorder in children.
The results, published Monday in the journal JAMA Pediatrics, add to growing evidence that the active ingredient in Tylenol may influence brain development in utero. But they do not provide clear answers for mothers-to-be or their doctors about whether acetaminophen is safe during pregnancy.
In analyzing data on more than 64,000 Danish women and their children, researchers found that kids whose mothers took the painkiller at any point during pregnancy were 29% more likely to be diagnosed with ADHD than were kids whose mothers took none. The risk increased the most — by 63% — when acetaminophen was taken during the second and third trimesters, and by 28% when used in the third trimester alone. But when taken only in the first trimester, the added risk was 9%.
The findings do not establish that prenatal exposure to acetaminophen — which is also an ingredient in Excedrin and is known in Europe and other parts of the world as paracetamol — caused the observed increase in hyperactivity disorders. But they underscore that medications are only "safe" for pregnant women until studies become sensitive enough to detect subtle problems, said Dr. Daniel Kahn, a UCLA obstetrician who was not involved in the research.
"We used to count a baby's 10 fingers and 10 toes and assume that any drug his mother took must have been safe," said Kahn, a specialist in fetal-maternal health. Now observational studies like this are capable of picking up on possible drug effects that are less obvious and harder to measure. As such research moves forward, he said, it's best to follow a "less is better" rule when it comes to taking medications during pregnancy.
"The lowest exposure is always the best, for any agent," Kahn said.
Even so, the study results wouldn't dissuade him from recommending Tylenol to a patient with a fever, because an unchecked fever during pregnancy has been linked to lower IQ in children, he said.
An editorial published alongside the report also cautioned that physicians and pregnant women would be wrong to change their practices on the basis of one study alone.
Without more details on how acetaminophen might lay the foundations for ADHD, and when and in whom it is most likely to boost risk, the current findings "should be interpreted cautiously," wrote the editorialists, led by neuropsychologist Miriam Cooper of the University of Cardiff in Wales.
Still, the link found in Denmark underscores that "the safety of some medications during pregnancy should not unquestioningly be considered absolute."
Members of the research team had long suspected that acetaminophen may behave as an endocrine-disrupting chemical capable of influencing fetal brain development, said Dr. Beate Ritz, chair of the department of epidemiology at UCLA's Fielding School of Public Health and one of the study's senior authors.
The drug is known to cross the placental barrier between mother and fetus, and some studies have found higher rates of male babies with undescended testicles born to women who took it during pregnancy.
A Norwegian study published in October found that when a mother gave birth to a child after having taken acetaminophen during pregnancy, that child was more likely to have developmental problems relating to movement, dexterity and communication than was a sibling born after an acetaminophen-free pregnancy.
Children exposed to the drug in utero were also more likely to have behavior and emotional difficulties, including shyness and anxiety, according to the report in the International Journal of Epidemiology.
The likelihood of a child having these emotional and developmental problems rose and fell along with the number of times his or her mother took acetaminophen during her pregnancy with that child, the report said.
"Pregnancy is such a sensitive period, and the development of the fetal brain is so vulnerable to disruption," Ritz said. "So much can go wrong," she added, particularly for males, whose incidence of neuropsychiatric disorders such as autism and ADHD is higher than that for girls.
The international research team, led by Dr. J¿¿rn Olsen, an epidemiologist at the University of Aarhus in Denmark, tracked the study's pediatric subjects from their first trimester of gestation for as long as 15 years. In addition to surveying parents about their children's behavior, they tapped into Denmark's comprehensive and reliable registries of physician diagnoses and dispensed pharmacy prescriptions to glean an accurate measure of ADHD in the population.
The study design averted a problem known as "recall bias" by gathering details on acetaminophen use long before signs of ADHD would become evident. Researchers did not ask pregnant subjects to detail how much or how often they took acetaminophen, but they interviewed them at the end of every trimester to gauge their use of the analgesic. That allowed the team to discern that the timing of a woman's acetaminophen use is likely to be important to fetal brain development.
"This is certainly one of the better studies we could ever do on the subject," Ritz said.
Overall, about 55% of the mothers took acetaminophen at some point during their pregnancy, the researchers found. Based on parents' assessments of their children's emotional, social and learning strengths and weaknesses over a six-month period, the baseline incidence of ADHD-like behaviors in children who weren't exposed to acetaminophen in utero was about 2.5%. Among those who used the medication at some point during pregnancy, the rate was 3.4%.
The international team that conducted the study will next investigate their data for evidence of the neuropsychiatric and other mental health effects of a variety of medications taken during pregnancy. Among the outcomes they will be looking for is autism.