The trouble with Tylenol and pregnancy

If you’re a pregnant woman and have a backache or headache, or a fever, your options for overthe-counter treatment basically boil down to one medication: the pain reliever acetaminophen, better known as Tylenol. Doctors advise against using nonsteroidal anti-inflammatories, like ibuprofen and aspirin, during late pregnancy because they can compromise fetal circulation and have other adverse consequences. But evidence has accumulated that, when taken during pregnancy, acetaminophen may increase the risk that children will develop asthma or attention deficit hyperactivity disorder. The elevated risk in most studies is small, and whether the drug itself is really to blame is debatable. But considering that more than 65 percent of pregnant women in the United States use acetaminophen at some point during their pregnancy, the number of children with problems stemming from it could be substantial.

The odd thing about acetaminophen is that even after decades of widespread use, no one knows precisely how it blunts pain. But it has earned a reputation for strange side effects. Experiments indicate that it impedes people’s ability to empathize. It may undercut the brain’s ability to detect errors. When taken after a vaccine, it may suppress the immune system. Why might the drug affect both asthma and ADHD rates? Scientists have variously speculated that it could tweak the immune system during pregnancy, or disrupt hormones, or change growth factors in the developing brain. In short, no one knows.

It’s the only thing pregnant women can take. But is it entirely safe?

The prevalence of asthma doubled between 1980 and 2000. At the same time, worries over Reye’s syndrome, a rare complication in children who take aspirin, led to a rise in the popularity of acetaminophen. On the basis of this circumstantial – and rather weak – evidence, 16 years ago, scientists at King’s College London proposed a link between rising acetaminophen use and the so-called asthma epidemic. Their reasoning was that acetaminophen depleted the body’s native antioxidant, called glutathione, spurring inflammation of the lungs.

Numerous studies followed showing an association with asthma, but they often relied on mothers’ potentially unreliable memories of what they took, or simply compared one group – mothers of asthmatic children, say – to a control group, a suboptimal study design.

Recently, however, much stronger studies showing a link have emerged. A study of Norwegian women and children published this year in the International Journal of Epidemiology found that prenatal acetaminophen use increased 7-year-olds’ risk of asthma by 13 percent.

Then, in August, a JAMA Pediatrics study on a British cohort noted that a mother’s use of the pain reliever in midpregnancy increased 7-year-olds’ risk of hyperactivity by 31 percent.

Of course, some familial trait may push people to reach for acetaminophen, and this quality, as opposed to the drug itself, may explain the increased risks. But that doesn’t seem to be the case. A mother’s use after she gave birth wasn’t associated with more problems in the British and Norwegian studies. Nor was a father’s.

Still, the authors are the first to note that perhaps they missed something. They don’t always know how much of the drug women take, or why they’re taking it. And there are reasons to think that the infections whose symptoms women might be treating with the pain reliever could themselves increase the risk of asthma and developmental problems. And yet these and some previous studies controlled for infections, and the association remained.

Not all of the research has confirmed the relationship. But at this point, the number of strong studies that do find a link are hard to overlook, and are unnerving.

Moreover, there’s evidence that the drug interacts more strongly with certain genotypes. Some of us carry gene variants that naturally alter the activity of the antioxidant glutathione, reducing its ability to detoxify. A 2010 study by Columbia University scientists found that, at age 5, the children with this variant, whose mothers had taken acetaminophen while pregnant, had double the risk of wheezing compared with children without the gene. In fact, without the gene, children had no increased risk of wheezing. So perhaps only a subset of people are vulnerable to the drug’s harmful effects.

Petra Arck, a professor of fetal-maternal medicine at the University Medical Center Hamburg-Eppendorf, and colleagues gave the pain reliever to pregnant mice, and found it stressed the liver, altered the placenta and increased the pups’ vulnerability to wheezing.

During pregnancy, the immune system must tolerate the fetus, which is half foreign, while also retaining enough firepower to fend off pathogens. Arck argues that the drug can interfere with this balancing act.

But two other mouse studies found no such effect on asthma or behavior. A major difference is the amount of acetaminophen given to the animals. Arck used a big dose. The other two studies used less.

Antonio Saad, a researcher at the University of Texas Medical Branch at Galveston whose own study failed to produce ADHD-like symptoms in mice, thinks that Arck used an unrealistically high amount. But the dose was intentional, Arck told me. Acetaminophen is in hundreds of medications, making it easy for pregnant women to take too much. Arck thinks some women overdose without knowing it.

Last year, the Food and Drug Administration reviewed evidence on acetaminophen and developmental outcomes and deemed it “inconclusive.” That was before the more recent studies appeared. When I asked, an FDA spokeswoman told me that the FDA was “actively reviewing” the new research. A spokeswoman for Johnson & Johnson, the maker of Tylenol, said the company wasn’t aware of evidence showing a “causal link” between prenatal use and later problems, but recommended discussing risks and benefits with a doctor.

The greater problem is that the kind of study that would definitively answer the prenatal acetaminophen question – a trial on pregnant women – is unlikely to happen, because such studies are generally considered unethical.

This leaves mothers-to-be awash in uncertainty when contemplating a drug that’s widely recommended. So what to do? No one I spoke with proposed they avoid acetaminophen outright. There’s nothing else to take. And untreated fever during pregnancy can have severe consequences, premature birth among them.

Instead, experts suggested that women use the minimum amount possible. Augusto Litonjua, a pulmonologist at Harvard Medical School who follows the research, noted that if women found themselves taking lots of acetaminophen, maybe they should consider non-pharmacological approaches to pain management, like acupuncture or meditation. For what it’s worth, in the recent JAMA Pediatrics study, the No. 1 reason for taking acetaminophen wasn’t infection or more severe problems, but backache. So maybe women’s partners should offer more massages, although that’s unlikely to help women dealing with serious pain.

The broader takeaway, said Evie Stergiakouli, lead author on the JAMA study, is that just because acetaminophen is easy to acquire doesn’t mean it’s not a drug, and that it doesn’t have potential side effects.

Moises Velasquez Manoff is the author of ‘An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases’ and a contributing opinion writer.