1. After adjusting for potential confounders, long-term maternal use of acetaminophen during pregnancy demonstrated an association with ADHD in offspring, though the association was offset when accounting for multiple confounding factors.
2. Long term paternal use of acetaminophen 6 months prior to conception was associated with increased rates of ADHD diagnoses in offspring.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Though acetaminophen is the recommended medication for pregnant women with fevers or pain, previous studies have raised concern for a potential connection between acetaminophen use during pregnancy and the development of ADHD in offspring. To evaluate this possible link, researchers completed a large prospective cohort study examining acetaminophen use in pregnancy, evaluating duration of use, indication for use, maternal preconception use, and paternal preconception use. Possible confounders such as co-medication use, maternal smoking and drinking, maternal anxiety and depression, maternal body mass index (BMI), and paternal or maternal ADHD symptoms were also considered. Long-term acetaminophen use, defined as 29 days or more, was associated with a significant increase in likelihood of children developing ADHD. This association was significant even after adjusting for only parental ADHD symptoms, though was not multiple confounding factors were considered. The association between long-term acetaminophen use and ADHD in offspring was increased when women reported using the drug for fever/infection or pain, as compared to those women not reporting a specific indication for use. Paternal use for greater than 7 days 6 months prior to pregnancy was also associated with a significant increase in offspring ADHD diagnoses. In contrast, short-term maternal intrapartum use, defined as 1-7 days, was associated with a slight decrease in ADHD diagnosis rates. While the study finds strength in its large data pool, the pathophysiology of this association was not explored and major findings were not significant after adjusting for confounders.
In-Depth [prospective cohort]: Researchers used data regarding acetaminophen use during pregnancy from the Norwegian Mother and Child Cohort study. All women in Norway were sent a survey at 18 weeks gestation from 1999 to 2009 and 40.6% consenting to participate in follow up surveys. Women were then asked the number of days of acetaminophen use, gestational age at time of use, indication for use, and use prior to pregnancy. Other potential confounders including simultaneously-used medication, maternal alcohol and tobacco use, maternal depression and anxiety, maternal BMI, and maternal or paternal symptoms of ADHD were controlled for. Data regarding ADHD diagnoses in offspring were gathered from the Norwegian Patient Registry and included all those diagnosed with a “hyperkinetic disorder” after age 3. Of the 112 973 children included, 2246 were diagnosed with ADHD. After adjusting for confounders, hazard ratios for trimester use were as follows: no use in any trimester, 1.00 (reference); use in any trimester, 1.06 (95%CI 0.96-1.19); use in any 2 trimesters, 1.22 (95%CI 1.07-1.38); use in all 3 trimesters, 1.27 (95%CI 0.99-1.63). Hazard ratios for short-term versus long-term use included: 1-7 days use, 0.90 (95%CI 0.75-1.09) versus 29 days or more, 2.20 (1.50-3.24). Paternal use of acetaminophen 6 months before pregnancy and for more than 7 days was associated with a significant increase in ADHD diagnosis rates with increasing duration of use, as follows: 1-7 days, HR 1.10 (95%CI 0.92-1.30); 8-28 days, 1.81 (95%CI 1.26-2.60); 29 days or more, 2.06 (95%CI 1.36-3.13).
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