Long-Term Use of Acetaminophen in Pregnancy Linked to ADHD Risk in Study

Use of acetaminophen for fever or pain is recommended for pregnant women over alternatives, and is used by about two-thirds of pregnant women in the United States. But new study from Norway finds that while short-term use presents no harm, long-term use of acetaminophen is associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring.

Surprisingly, the link comes not just with a pregnant mother’s use of the pain reliever, but with a father’s use as well, the results show. However, the authors acknowledge that the results might be questioned because the ADHD diagnoses were not independently confirmed.

The findings, published in the journal Pediatrics, are based on an examination of data from the Norwegian Patient Registry, which collected information from 112,973 babies born between 1999 and 2009, including 2246 with ADHD. The researchers adjusted for a mother’s use of acetaminophen before pregnancy and family history of ADHD. They found that if a mother used acetaminophen for a week or less during pregnancy, their babies were 10% less likely to be diagnosed with ADHD.

However, if the mother took acetaminophen for more than 29 days during pregnancy, the risk of an ADHD diagnosis was 220% higher.

Nearly half—47%—of the mothers in the study used acetaminophen at some point in the study; 27% used the pain reliever in 1 trimester and 16% used it in 2 trimesters. Only 4% used it in all 3 trimesters.

Curiously, while mothers’ use of acetaminophen during pregnancy was linked to higher ADHD rates, use before pregnancy was not. But long-term use of the pain reliever by fathers was tied to higher ADHD rates. The authors could only speculate on the reason: “It may be due to male germ-line epigenetic effects as described in endocrine disruption effects of acetaminophen on the human testes.”

The authors gave 3 possible reasons why long-term use of acetaminophen by mothers in pregnancy could be linked to ADHD:

1. Based on experiments with mice, it might alter levels of neurotropic factors, lower fear responses and reduce learning abilities in adulthood
2. It can interfere with maternal hormones related to fetal development
3. It could interrupt brain development by bringing on oxidative stress, causing neuron death

More animal studies would offer insights into these theories. But the researchers acknowledged a major limitation of the study: the diagnoses were not validated in a clinic. Thus, it is possible that codes were used in some cases when children had language problems or other developmental issue that were not ADHD.

In an accompanying editorial, Mark L. Wolraich, MD, pointed out that the authors are careful to note that they cannot point to a causal relationship, and more studies are needed. But the large size of the data set shows the need for careful consideration of acetaminophen use during pregnancy.

“It is important to pursue further research on the possible drug associations with the development of ADHD, and that research will require longitudinal follow-up of large numbers of children with and without ADHD,” he wrote.

Reference

Ystrom E, Gustavson K, Brandlistuen RE, et al. Prenatal exposure to acetaminophen and risk of ADHD [published online October 30, 2017]. Pediatrics. 2017; e20163840; DOI: 10.1542/peds.2016-3840