Mothers' use of acetaminophen during pregnancy linked to ADHD in children

Mothers who took acetaminophen for more than 29 days during pregnancy had more than double the risk of a child diagnosed with attention-deficit/hyperactivity disorder (ADHD), according to a study published in Pediatrics. This association remained after adjusting for the mother’s use of acetaminophen before pregnancy, indications for analgesic use, and familial risk for ADHD, the researchers reported.

Fathers who used acetaminophen for 29 days or more also had a two-fold greater risk of having a child with ADHD.

But, the investigators stopped short of concluding that acetaminophen causes ADHD. “[G]iven that paternal use of acetaminophen is also associated with ADHD, the causal role of acetaminophen in the etiology of ADHD can be questioned. We do not provide definitive evidence for or against a causal relation between maternal use of acetaminophen and ADHD,” cautioned the authors, led by Eivind Ystrom, PhD, of the Norwegian Institute of Public Health, Oslo, Norway.

In previous studies, these and other researchers have suggested a link between prenatal use of acetaminophen and a diagnosis of ADHD in children.

“In contrast to previous studies, we were able to adjust for indications of acetaminophen use and parental symptoms of ADHD,” the researchers wrote. “We were furthermore able to analyze maternal use of acetaminophen prior to pregnancy as a specificity control and to estimate the effect of paternal use prior to pregnancy.”

In this study, Dr. Ystrom and colleagues reviewed patient data on nearly 113,000 children and their parents from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. This included 2,246 children diagnosed with ADHD.

Mothers who participated in the Norwegian birth cohort study filled out two questionnaires, one at about 18 weeks of pregnancy and one after delivery. These included specific questions about medical conditions, use of acetaminophen and other medications, the medications’ indications for use, and the number of days the medications were used. Fathers completed a separate questionnaire at about 18 weeks of pregnancy that asked about their medication use for the last 6 months before pregnancy.

Results showed nearly 47% of women (52,707) took acetaminophen during pregnancy—27% used it in only one trimester, 16% used it in two trimesters, and 3.3% used it in all three trimesters.

After adjusting for potential confounders, the researchers showed that mothers’ use of acetaminophen before conception was not associated with ADHD. Also, maternal use of acetaminophen for less than 8 days during pregnancy was negatively associated with having a child with ADHD (HR = 0.90; 95% CI 0.81-1.00). This finding indicates that the drug’s antipyretic effect could benefit fetal development, the researchers suggested.

However, maternal acetaminophen used for 29 days or more during pregnancy was associated with a two-fold increased risk of ADHD (HR = 2.20; 95% CI 1.50-3.24), even after adjusting for confounders and regardless of why mothers took the drug. Likewise, fathers who used acetaminophen for 29 days or more during the pregnancy also had a two-fold increased risk of ADHD in their children (HR = 2.06; 95% CI 1.36-3.13).

Furthermore, mothers who used acetaminophen specifically for fever and infections for 22 to 28 days of pregnancy had a six-fold greater risk of having a child with ADHD (HR = 6.15; 95% CI 1.71-22.05).

“Long-term maternal use of acetaminophen during pregnancy is associated with ADHD in offspring,” the authors concluded. “This holds true even after adjusting for potential confounders, including parental symptoms of ADHD and indications of acetaminophen use.”

The researchers proposed three hypotheses to explain the association between maternal acetaminophen use and ADHD:

• Exposure to acetaminophen in utero modifies levels of brain-derived neurotropic factor in mice, resulting in altered behavior, lower fear responses, and reduced learning abilities in adulthood.

• Acetaminophen could alter maternal hormones related to fetal brain development, including thyroid and sex hormones.

• Acetaminophen could induce oxidative stress that may result in the interruption of brain development, and cause neuronal death.

All three of these possible mechanisms could be tested in experimental animal studies, the researchers recommended.

In an accompanying editorial, professor of pediatrics Mark L. Wolraich, MD, Child Study Center, University of Oklahoma, Oklahoma City, OK, observed: “The authors are careful to point out that their results from a relational study cannot establish a causal relationship between prenatal acetaminophen exposures and ADHD in the offspring, but they do suggest the possibility and raise the need for further study and more cautious consideration of acetaminophen use during pregnancy.”