More support for ADHD and acetaminophen use in pregnancy connection

Xiaobin Wang, MD, MPH, ScD

There are new concerns about acetaminophen use in pregnancy, according to a report that linked maternal acetaminophen use to a higher risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) in their children.

The results of the study, conducted by researchers at the Bloomberg School of Public Health at Johns Hopkins University in Baltimore, Maryland, was published in JAMA Psychiatry, and sought to investigate whether there was an association between cord plasma biomarkers of in utero acetaminophen exposure and later development of ADHD or autism. The team investigated 996 mother and child pairs from the Boston Birth Cohort, measuring fetal exposure through cord plasma. The study was based on previous research that raised concerns about maternal acetaminophen use during pregnancy being linked to these disorders, but most prior studies relied on maternal reporting alone.

Acetaminophen is one of the most commonly used medications for pain and fevers, and has generally been regarded as safe during pregnancy. According to the report, more than 65% of women in the United States and 50% in Europe use acetaminophen during pregnancy. However, recent studies in both animals and humans linking acetaminophen use to a variety of adverse outcomes during childhood-including asthma, neurodevelopmental disorders, and more-have spurred research into its use. Some research has linked acetaminophen toxicity in cortical neurons and inhibition of fetal testosterone production to a disruption in brain development. Acetaminophen crosses the placental barrier, and can remain in an infant’s blood circulation for a long time, the report notes, and research into the long-term effects of this exposure have increased in recent years. Policy makers and research organizations have refrained from making recommendations regarding acetaminophen use during pregnancy, however, citing limited evidence and recall bias from studies based on maternal reporting. This study is the first to take a physiological approach to measuring acetaminophen exposure and its effects, and demonstrates a need for ongoing investigation.

Xiaobin Wang, MD, MPH, ScD, Zanvyl Kriefger professor, director of the Center on Early Life Origins of Disease at the Johns Hopkins University Bloomberg School of Public Health, and one of the authors of the report, says the results of the study were not particularly surprising.

“Our study was motivated by previous studies in various populations that have raised concern about maternal self-reported acetaminophen use on child risk of ADHD and autism,” Wang says. “Our findings corroborate with previous studies and warrant additional investigations.”

In this new study, the research team tested 3 cord metabolites of acetaminophen-unchanged acetaminophen, acetaminophen glucuronide, and 3-[N-acetyl-l-cystein-S-yl]-acetaminophen-collected at birth. Researchers found that of the 996 participants, the final sample included 257 (25.8%) of children with ADHD only; 66 (6.6%) with ASD only; 42 (4.2%) with both ADHD and ASD; 304 (30.5%) with other developmental disabilities; and 327 (32.8%) that were neurotypical. Unchanged acetaminophen levels were detectable in cord blood samples for the entire cohort, according to the report. The study concludes that, based on the evidence found in this study group, that fetal acetaminophen exposure is associated with a significantly increased risk of childhood ADHD and ASD. Although the report doesn’t go as far as to make clinical recommendations on acetaminophen use during pregnancy, researchers do suggest that additional investigation of prenatal and perinatal acetaminophen exposure is warranted.

One area that needs more research, Wang says, is exposure to acetaminophen earlier in pregnancy.

“Because our study only measured acetaminophen and its metabolites in fetal cord blood at birth, it is likely only catching exposure close to delivery,” Wang says. “Future studies should further improve exposure assessment by collecting periodic biomarker samples throughout pregnancy and accurately document mother’s use of acetaminophen including timing and dose.”

Although there have been no official recommendations from groups like the Society for Maternal-Fetal Medicine, which designated acetaminophen as “reasonable and appropriate” for use during pregnancy due to inconclusive evidence to the contrary, Wang says he encourages clinicians to discuss the risk versus the benefits with patients.

“In the past, acetaminophen use during pregnancy was considered to be safe,” Wang says. “Our findings, along with previous studies, raise the concern about the potential risk of acetaminophen use during pregnancy. Before it is certain, this information helps the women and their providers to weigh the benefit and potential risk of acetaminophen use during pregnancy and make informed decisions.”