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Prenatal acetaminophen use may increase ADHD risk in offspring

Jairia Dela Cruz
14 Nov 2017

Long-term use of acetaminophen during pregnancy poses a more than twofold increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring, a study has found.

Results of the study involving 112,973 offspring from the Norwegian Mother and Child Cohort Study, including 2,246 with ADHD, revealed a modest association between ADHD and any prenatal maternal use of acetaminophen during the first (hazard ratio [HR], 1.07; 95 percent CI, 0.96 to 1.19), second (HR, 1.22; 1.07 to 1.38) and third trimesters (HR, 1.27; 0.99 to 1.63). [Pediatrics 2017;doi:10.1542/peds.2016-3840]

The observed association was already adjusted for acetaminophen use prior to pregnancy and for parental symptoms of ADHD. But even more interesting was that when duration of prenatal acetaminophen use was analysed, a week of exposure to the drug was negatively associated with offspring ADHD risk, which however increased as the number of days exposed to the drug increased.

Specifically, maternal use of the drug for ≥29 days increased the risk of ADHD in offspring by 2.20 times (1.50 to 3.24). In contrast, use for <8 days yielded an HR of 0.90 (0.81 to 1.00). Acetaminophen use in the treatment of fever and infections for 22 to 28 days was strongly associated with offspring ADHD risk (HR, 6.15; 1.71 to 22.05).

A similar pattern of association was observed for paternal acetaminophen use. Paternal use for ≥29 days in the 6 months before pregnancy was just as strongly associated with offspring ADHD (HR, 2.06; 1.36 to 3.13) as the corresponding maternal prenatal use.

“ADHD is highly familial in both children and adults… With our analyses, we showed that the association between maternal acetaminophen use and ADHD did not appear to be strongly confounded by common familial (eg, genetic) factors for ADHD and use of acetaminophen,” the authors said. [Psychol Med 2014;44:2223–2229]

The authors added that the association between maternal acetaminophen use and ADHD may be explained by at least three plausible hypotheses. First, as shown in animal studies, neonatal exposure to acetaminophen changes the levels of brain-derived neurotropic factor, which promotes neuronal survival and regulates cell migration, axonal and dendritic outgrowth and formation of synapses. [Toxicol Sci 2014;138:139–147; Mol Neurobiol 2006;33:155–179]

Acetaminophen can also interfere with maternal hormones, including thyroid and sex hormones, which are related to foetal brain development. Furthermore, the drug may interrupt brain development through induction of oxidative stress, leading to neuronal death. [JAMA Pediatr 2014;168:313–320; Int J Epidemiol 2013;42:1702–1713]

On the other hand, the mechanisms by which paternal acetaminophen use before pregnancy increase the risk of offspring ADHD are unclear, although it could be due to male germ-line epigenetic effects as described in endocrine disruption effects of acetaminophen on the human testis. [Hum Reprod 2013;28:1890–1898; J Clin Endocrinol Metab 2013;98:E1757–E1767]

In a linked editorial, Dr Mark L. Wolraich from the University of Oklahoma in US highlighted the benefit of using a large data set in establishing a relationship between prenatal acetaminophen use and ADHD. [Pediatrics 2017;doi:10.1542/peds.2017-2703]

The present study demonstrates “how it is possible to more specifically examine the possible association between prenatal exposure to acetaminophen and ADHD. [It was] able to use statistical techniques that required a large number of individuals with the condition,” Wolraich said, noting the great deal of variation in the presentation of ADHD.

While the study authors are careful to point out that their results from a relational study cannot establish a causal relationship between prenatal acetaminophen exposures and offspring ADHD, their findings “do suggest the possibility and raise the need for further study and more cautious consideration of acetaminophen use during pregnancy,” he added.

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