Caution on chronic, high-dose use of acetaminophen in pregnancy

Children born to women who used acetaminophen during pregnancy could be at increased risk for several behavioural problems, a new British study suggests, adding to the controversy about what is safe to take for pain and fever when expecting.

Acetaminophen, found in Tylenol and in generic form, is generally considered safe in all stages of pregnancy because it doesn't have the same risks as other painkillers consumers can grab off the shelf. 

But large studies following birth outcomes in Denmark and New Zealand have suggested the use of acetaminophen in pregnancy may be associated with behavioural problems. In animal models, the drug seems to disrupt endocrine function and brain development.

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To understand why this risk seems to occur, the British researchers set out to test if using acetaminophen during pregnancy may cause changes in the womb, or to check if other factors common to a family, such as behavioural or social factors, could be playing a role. 

They followed about 14,000 pregnant women who were expected to deliver in 1991 or 1992. They collected detailed information, through clinical visits and questionnaires, about the health and development of the children until the age of seven and about genetic risk factors.

"What we show is that the only time that acetaminophen use was associated with behavioural difficulties was when it was used during pregnancy," said study author Evie Stergiakouli, a lecturer in epidemiology at the University of Bristol in England. 

"Basically, we examined acetaminophen used at 18 weeks of pregnancy so around the second trimester and also at the 32 week, so around the 3rd trimester. We saw acetaminophen use associated with conduct disorder and hyperactivity symptoms at 18 weeks and at 32 weeks also emotional problems as well as conduct symptoms, hyperactivity symptoms and a score of total behavioural difficulties."

Among those whose mothers took the drug during the third trimester, about six out of 100 had behavioural difficulties compared with four out of 100 among those whose mothers did not take the drug. 

There was no association with the woman's use of acetaminophen after giving birth or a partner's use.

The study participants were asked if they'd used acetaminophen in the previous three months. The researchers did not have any information on the dose taken or for how long. 

At 18 weeks of pregnancy, 4,415 mothers, or 53 per cent of them, reported using acetaminophen. At 32 weeks, 3,381 mothers, or 42 per cent, said they did.

The research is published in Monday's issue of the journal JAMA Pediatrics. 

Not treating fever, pain during pregnancy a risk

The findings suggest the association may be due to direct biological effects on the fetus, she said in an interview. 

The widespread use of acetaminophen during pregnancy worldwide could mean the findings have important implications for public health, Stergiakouli said. But more research is needed to understand the mechanism and to test alternative explanations. 

"Women should still use acetaminophen when required in pregnancy and according to their physician's advice, and this is because there is a risk to the fetus of not using acetaminophen when it is required. For example, fever during pregnancy can be quite dangerous and can lead to pre-term labour," Stergiakouli said. 

The study is well-done, potentially important, but controversial, said Dr. Michael Rieder, a clinical pharmacologist and professor of pediatrics at Western University in London, Ont. He was not involved in the study.

More research required

As the study's authors themselves say, the lack of data on dose and duration is problematic, Rieder said.

"The use of occasional acetaminophen in the first trimester of pregnancy is almost certainly not a cause for alarm," Rieder said in  an email. "Women should not be worried about these exposures."

In the second and third trimesters, the issue is which drug to use for pain or fever. Non-steroidal anti-inflammatory (NSAID) drugs such as ibuprofen, found in Advil and generic forms, are an option, Rieder said. The caveat is that NSAIDs should not be used in the late third trimester because they can interfere with how the newborn's heart and lungs adapt to life outside the womb.

The study doesn't prove acetaminophen causes developmental issues in children.

"Women shouldn't panic about this finding," said Dr. David Juurlink, head of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto.

"There's a lot of uncertainty about whether or not acetaminophen really does cause any sort of harm to the developing brain, but the possibility exists that it might. I think in light of that, especially when coupled with what we know about acetaminophen's beneficial effects, which are minimal, I have a hard time recommending women take acetaminophen during pregnancy. I think they should consider taking something else or perhaps even nothing at all."

It's a discussion women who are pregnant or who are considering becoming pregnant should have with their physician, Juurlink said. 

Aliya Visram is an acupuncturist and chiropractor who specializes in prenatal and postnatal care in Toronto. She's also expecting her second child.

Based on her clients, Visram estimates about half of pregnant women experience back pain. "For me, the bottom line is stay active," such as by walking, swimming or doing yoga.

The study was funded by the Medical Research Council.