A migrant worker from Mexico brings her 18-month-old to the doctor with a fever. The doctor suggests Tylenol to help reduce the fever. “But doesn’t it cause the cough?” she asks. “How did she know that?” the doctor asks himself.
The fact is, since introduced in 1953, acetaminophen has never been subjected to a clinical trial to demonstrate its long-term safety for children. In the early 1980s, by which point Tylenol already matched aspirin in sales, the CDC warned against using aspirin for chicken pox or flu. Aspirin was linked with Reye's Syndrome, a neurologic disorder that develops after certain viral infections, and Tylenol became the dominant analgesic recommended for children. At the very same time, rates of asthma have risen markedly. A study published in 1998 noted the association between the decline in aspirin and the rise in acetaminophen and asthma- see the graph below. Asthma affects about 7% of the US population and an estimated 4.5% worldwide.
The team selected the 19 most consistent studies comprising 425,000 adults and children in countries across the globe. Overall, they found that the population had 1.6 times worse odds of developing asthma with acetaminophen use- either prenatally, in the first year of life, or in the year prior to diagnosis. Put another way: If we suppose that 4% of the population not exposed to acetaminophen would develop asthma, then 6.3% of the population that uses acetaminophen would get asthma.
The biggest study that looked at acetaminophen and asthma is the International Study of Asthma and Allergies in Childhood, or ISAAC. ISAAC investigators interviewed parents of over 200,000 children ages 6 to 7 in 31 foreign countries, and asked how frequently children had used acetaminophen both in their first year of life and in the most recent 12-month period: never, at least once per year ("medium"), or at least once per month ("high"). ISAAC researchers attributed 22% of asthma cases at ages 6-7 to acetaminophen used (medium or high) in the first 12 months of life and attributed 40% of asthma cases to current use of acetaminophen. The study attributed 38% of severe asthma cases to medium acetaminophen use. Most convincingly, high users of acetaminophen in the most recent 12-months were three times more likely to report asthma than non-users.
These are strong statistical correlations. Because the link held similarly across 31 countries in both hemispheres, where different kinds of illnesses would spur the use of acetaminophen, this removes some of the doubt about confounding the link between asthma and acetaminophen. However, doctors and skeptics still wonder: could it just be that the people who have asthma would tend to use acetaminophen more often, and that the relationship isn’t causal?
A clinical trial would answer doubts more conclusively. So far, there has been only one, which looked at asthma and ibuprofen versus acetaminophen in 1,900 US children in 1992-3. The double-blind study actually set out to find increased risks of asthma with ibuprofen use, but it ended up showing the contrary. The study showed that treatment with ibuprofen led to approximately half as many outpatient visits for asthma as acetaminophen. It also tracked asthma treatment or hospitalizations up to four weeks after treating fevers with ibuprofen. While the number of hospitalizations for asthma was too few for statistical significance, it was highest in the acetaminophen group.
So an association between acetaminophen and asthma has been shown in a variety of studies. As for trials to prove it decisively, there is just this one, which could be showing that ibuprofen is protective rather than that acetaminophen is harmful. But a November 2009 longitudinal study that brought in genomics research has clarified the picture.
When we take acetaminophen, it depletes cells' supply of a molecule called glutathione, a common, widespread molecule in our cells. Glutathione is important for protecting cells from oxidizing stresses. Glutathione waits in its reduced form to bind with a reactive oxygen molecule. In other words, glutathione is an important anti-oxidant. If the cells can't make enough reduced glutathione to detoxify acetaminophen and protect against other cell stressors, then damage to cells can occur.
It is well known that inner-city populations of Dominican, Puerto Rican, and African-American children have shown high rates of asthma. There has been a huge effort to find genetic or other factors to explain the rise in asthma incidence among these populations. One finding is that populations hardest hit with asthma have enzymes that are less efficient than other populations at reducing glutathione, caused by a polymorphism in the Glutathione S-transferase gene called GSTP.
The GSTP polymorphism has been seen in 43-44% of African-American and Latino populations. Though less so, it is still common in other populations: 32% of Caucasians in the US and UK, 33% of Swedes, and 18% of Taiwanese. Researchers from Columbia University followed a cohort of African American and Dominican-origin mothers since pregnancy. They tracked their use of acetaminophen during pregnancy and asthma symptoms in their children through age 5. The children overall were over 70% more likely to have asthma if their mothers used any acetaminophen- even one dose- during their pregnancy.
Risks were higher as the dosages increased. Once the researchers separated the children with the GSTP polymorphism from those without it, they found that the risks of asthma with acetaminophen were present only for these children—at a rate of twice as likely as non-users of acetaminophen. And they found no significant risk from acetaminophen in the children without the GSTP polymorphism.
There is certainly plenty of opportunity for researchers to better understand the cell injuries that trigger asthmatic pathways in the lungs. However, caution from doctors and the public on the use of acetaminophen, especially by children and pregnant women, seems overdue.
