We can date our pregnancies by what we were told was safe that later turned out to be more problematic. My own mother often told me lovingly (and laughingly) of the understanding doctor who advised her to drink rum every night when she was pregnant with me and had trouble falling asleep. And we know that on balance, it’s a good thing that science and epidemiology march forward, with more careful and more thorough investigations of the possible effects of exposures during fetal development and their complex long-term implications.
But it’s disconcerting to learn that something you did, or something you took, in all good faith, following all the best recommendations, may be part of a more complicated story. And the researchers who have been examining the possible effects of fairly extensive acetaminophen use during pregnancy are very well aware that these are complex issues to communicate to women who have been pregnant in the past, who are pregnant right now or who become pregnant in the future.
Acetaminophen, found in Tylenol and many other over-the-counter products, has been the drug recommended for pregnant women with fever or pain or inflammatory conditions certainly as far back as my own pregnancies in the 1980s and ‘90s.
But in recent years there have been concerns raised about possible effects of heavy use of acetaminophen on the brain of the developing fetus. A Danish epidemiological study published in 2014 found an association between prenatal acetaminophen use during pregnancy and attention deficit hyperactivity disorder, especially if the acetaminophen use was more frequent.
Zeyan Liew, a postdoctoral scholar in the department of epidemiology at the U.C.L.A. Fielding School of Public Health, who was the first author on the 2014 article, said it was challenging for researchers to look at effects that show up later in the child’s life. “With a lot of drug safety research in pregnancy, they only look into birth outcomes or congenital malformations,” Dr. Liew said. “It’s very difficult to conduct a longitudinal study and examine outcomes like neurobehavioral disorders.”
Was the increased risk of attention problems caused by the acetaminophen, or to the conditions for which the mothers had taken the medication in the first place? Since A.D.H.D. is in part an inherited condition, was it possible that parents with attention problems and impulsivity were more likely to take medication?
In a large study published online in the journal Pediatrics in October, researchers looked at acetaminophen use during more than 100,000 pregnancies in Norway, and at the risk of the child’s eventually being diagnosed with A.D.H.D.
The same group had done an earlier, smaller study published in 2013 that showed children exposed to long-term use of acetaminophen had more neurodevelopmental issues at 3 years of age than their unexposed siblings. For example, they started walking later, and had more gross motor problems.
The researchers were skeptical of this finding, said Eivind Ystrom, a professor of psychology at the University of Oslo, and a senior researcher at the Norwegian Institute of Public Health, who worked on both studies and is the lead author of the new article.
“We expected to find nothing,” he said, and assumed that the difference could be explained by whatever illnesses or symptoms during the pregnancies had led to the acetaminophen use by the mother.
In their 2017 study of pregnant women, they had access to information collected from the mothers about all their symptoms during the pregnancy, including more than a hundred medical conditions, he said, as well as information about what other drugs they had taken while pregnant. And by linking that study to the Norwegian patient registry, they could see which children were later given A.D.H.D. diagnoses. They could also factor out all kinds of other health information, including whether the mother or the father had symptoms of A.D.H.D.
They could adjust statistically for smoking or depression, he said, as well as for all the different symptoms for which the women had taken the acetaminophen in the first place. And none of these adjustments affected the conclusion: “What we found was that regardless of the reason they used acetaminophen, those who reported long-term exposure — 29 consecutive days or more — had a more than twofold risk of A.D.H.D.”
And the effect was there for women who took the acetaminophen for different medical conditions, making it seem less likely that some particular medical problem was actually affecting the developing fetus.
“We really tried all the tricks in the book to remove this effect and we can’t make it go away,” Dr. Ystrom said. “It’s a problem because it’s a recommended drug for pregnant women.”
For women who used acetaminophen but only for less than seven days, the risk of A.D.H.D. actually went down — something else that the researchers cannot explain.
All this does not actually prove cause and effect. “Maybe those who used it for a very long time had more severe fever or more severe pain than those who didn’t use it,” Dr. Ystrom said. “That is the alternative explanation, that these mothers who used it for a long time, they had a more severe type of condition.”
But there’s enough evidence of a link to make experts think carefully — and argue — about what the recommendations should be. People who counsel pregnant women are legitimately concerned about the anxiety these studies can cause, while the science and epidemiology are still being figured out, but once the concern is out there, and the debate is going on, the people most directly affected are entitled to the information — and the anxiety.
So the study leaves scientists with “two conflicting things to communicate to the public,” Dr. Ystrom said. “Short term use, we have no reason to think it’s bad; long-term use, we have a twofold risk.”
The study cites research stating that 65 to 70 percent of women in the United States take acetaminophen during pregnancy, although the prolonged use of 29 days or more is a much rarer pattern. Researchers are also worried that women will be frightened out of using the medication when they need it, and will suffer through symptoms that can cause harm and distress to the mother, and potentially to the fetus as well. And there are not necessarily alternative safer drugs for pregnant women.
“Most pregnancies, short-term use is the only relevant use,” said Dr. Ystrom. “Our worry is that those who need to take the drug when they have fever don’t do it; that would be really bad.”
“Fever, pain, stress, those indications could also have adverse effects on the developing fetus,” Dr. Liew said. But the consistency of the association with acetaminophen means “there’s a reason to be cautious using it, not to assume it’s risk-free.”
We all want reliable guidance, especially when we’re pregnant. It’s disconcerting even to be reminded of how difficult it is to answer these questions. The complexities of pregnancy and medications and the many unanswered questions demand more research and more information, even while it leaves us less certain and perhaps less comfortable.
For now, pregnant women are left with the old advice: Talk to your doctor about managing pain and fever. But while those conversations may be a little more complicated than they used to be, those who end up needing occasional medication, which is not related to increased risk, should take comfort from the idea that such use is now being scrutinized much more carefully and more longitudinally than it was back when I was pregnant, and no one was talking about the possible long-term effects.
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