Prenatal exposure to acetaminophen ― a drug considered safe in pregnancy ― may raise the risk for behavioral problems in children, including attention-deficit/hyperactivity disorder (ADHD) and hyperkinetic disorder (HKD), a severe form of ADHD, new research suggests.

"Because the exposure and outcomes are frequent, these results are of public health relevance," the investigators write.

The findings "should inspire much more research and a cautious use of these drugs during pregnancy; they should only be taken when they are really needed," study investigator Jørn Olsen, MD, PhD, of the Institute of Public Health, University of Aarhus, Denmark, told Medscape Medical News.

The study was published online February 24 in JAMA Pediatrics.

Hormone Disrupter?

The premise of the study was that acetaminophen may act as a hormone disrupter and thus alter fetal brain development.

Dr. Olsen and colleagues analyzed data on 64,322 children and their mothers enrolled in the Danish National Birth Cohort (1996 - 2002). Acetaminophen use during pregnancy was assessed during pregnancy and 6 months after childbirth.

More than half of the women (56%) reporting using acetaminophen during pregnancy. Children with prenatal exposure to acetaminophen were at higher risk of being diagnosed with HKDs, using ADHD medications, or having ADHD-like behaviors.

Outcome Hazard Ratio 95% CI HKD 1.37 1.19 - 1.59 ADHD medication use 1.29 1.15 - 1.44 ADHD-like behavior 1.13 1.01 - 1.27

CI, confidence interval

For all outcomes, stronger effects were seen among children exposed to acetaminophen during more than 1 trimester and among those exposed for a greater number of weeks (P trend < .001).

The results did not appear to be confounded by maternal inflammation or infection during pregnancy, mother's mental health problems, or any of a number of other factors evaluated, the investigators report. However, they add that they cannot rule out residual confounding by genetic factors, unmeasured maternal psychopathology, exposure to other medications, or indication for drug use.

Interpret With Caution

Acetaminophen can cross the placenta barrier, and recent studies have suggested that maternal use of acetaminophen increases the risk for cryptorchidism in boys, owing to its endocrine-disrupting properties, the investigators note in their article.

"Maternal hormones, such as sex hormones and thyroid hormones, play critical roles in regulating fetal brain development, and it is possible that acetaminophen may interrupt brain development by interfering with maternal hormones or via neurotoxicity such as the induction of oxidative stress that can cause neuronal death," the researchers write.

If the current observations reflect causal associations, "acetaminophen should no longer be considered a safe drug for use in pregnancy," Dr. Olsen and colleagues conclude.

But the authors of an editorial published with the study emphasize that "causation cannot be inferred from the present observed associations" and that a replication study is needed.

For now, these "interesting" observations "should be interpreted cautiously and should not change practice," write Miriam Cooper, MRCPsych, of the Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, United Kingdom, and coauthors.

The findings "underline the importance of not taking a drug's safety during pregnancy for granted, and they provide a platform from which to conduct further related analyses exploring a potential relationship between acetaminophen use and altered neurodevelopment," they write.

The study was supported by the Danish Medical Research Council. One author on the study who contributed to the study when she was at University of Arizona currently works at Novartis Farmaceutica SA, Barcelona, Spain. No other disclosures were reported.

JAMA Pediatr. Published online February 24, 2014. Abstract, Editorial