To estimate the association between maternal use of acetaminophen during pregnancy and of paternal use before pregnancy with attention-deficit/hyperactivity disorder (ADHD) in offspring while adjusting for familial risk for ADHD and indications of acetaminophen use.
Diagnoses were obtained from the Norwegian Patient Registry for 112 973 offspring from the Norwegian Mother and Child Cohort Study, including 2246 with ADHD. We estimated hazard ratios (HRs) for an ADHD diagnosis by using Cox proportional hazard models.
After adjusting for maternal use of acetaminophen before pregnancy, familial risk for ADHD, and indications of acetaminophen use, we observed a modest association between any prenatal maternal use of acetaminophen in 1 (HR = 1.07; 95% confidence interval [CI] 0.96–1.19), 2 (HR = 1.22; 95% CI 1.07–1.38), and 3 trimesters (HR = 1.27; 95% CI 0.99–1.63). The HR for more than 29 days of maternal acetaminophen use was 2.20 (95% CI 1.50–3.24). Use for <8 days was negatively associated with ADHD (HR = 0.90; 95% CI 0.81–1.00). Acetaminophen use for fever and infections for 22 to 28 days was associated with ADHD (HR = 6.15; 95% CI 1.71–22.05). Paternal and maternal use of acetaminophen were similarly associated with ADHD.
Short-term maternal use of acetaminophen during pregnancy was negatively associated with ADHD in offspring. Long-term maternal use of acetaminophen during pregnancy was substantially associated with ADHD even after adjusting for indications of use, familial risk of ADHD, and other potential confounders.
Comments
RE: Prenatal Exposure to Acetaminophen and Risk of ADHD
Ystrom et al.(1) report an association between prenatal exposure to acetaminophen and the risk of ADHD. Risk of ADHD in offspring were compared using maternal acetaminophen never-user as the reference. They found an increased risk of ADHD among offspring of the mothers, who were exposed to acetaminophen during pregnancy, in a dose dependent pattern, and possible confoundings were corrected accordingly. The causal effect in an association study cannot be determined, and the link they identified is reminiscent of the long-term debate whether maternal exposure of selective serotonin reuptake inhibitor (SSRI) increases the risk of either autism spectrum disorder or ADHD in offsprings(2). Earlier this year a Swedish study by Sujan et al. used a novel approach to solve the issue of unaccounted-for confoundings(3). Each offspring was compared with their own sibling, when the mother was exposed to SSRI during only one pregnancy, but not in the other one. By this approach, they found no association between SSRI and ADHD. In the same article, they also demonstrated a strong association between SSRI and ADHD exists, if they used the traditional approach, that is, exposed mother compared with non-exposed mother, as seen in the article by Ystrom et al1. Confoundings beyond family history or indications of acetaminophen exist and are hard to be corrected. The increased risk might be due to maternal factors, e.g. sociodemographic status, chronic pain without documented diagnosis, that lead increased consumption of acetaminophen. Therefore, the title “prenatal exposure to acetaminophen and risk of ADHD” might cause unnecessary panic among expectant mothers, in which group the analgesic selection is already limited due to the concerns of risks.
References:
1. Ystrom E, Gustavson K, Brandlistuen RE, et al. Prenatal Exposure to Acetaminophen and Risk of ADHD. Pediatrics. November 2017:e20163840.
2. Clements CC, Castro VM, Blumenthal SR, et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry. 2015;20(6):727-734.
3. Sujan AC, Rickert ME, Öberg AS, et al. Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring. JAMA. 2017;317(15):1553–10.
RE: Prenatal Exposure to Acetaminophen and Risk of ADHD
Ystrom et al. (Oct. 2017 issue)(1) report an association between prenatal exposure to acetaminophen and the risk of ADHD. Risk of ADHD in offspring were compared using maternal acetaminophen never-user as the reference. They found an increased risk of ADHD among offspring of the mothers, who were exposed to acetaminophen during pregnancy, in a dose dependent pattern, and possible confoundings were corrected accordingly. The causal effect in an association study cannot be determined, and the link they identified is reminiscent of the long-term debate whether maternal exposure of selective serotonin reuptake inhibitor (SSRI) increases the risk of either autism spectrum disorder or ADHD in offsprings(2). Earlier this year a Swedish study by Sujan et al. used a novel approach to solve the issue of unaccounted-for confoundings(3). Each offspring was compared with their own sibling, when the mother was exposed to SSRI during only one pregnancy, but not in the other one. By this approach, they found no association between SSRI and ADHD. In the same article, they also demonstrated a strong association between SSRI and ADHD exists, if they used the traditional approach, that is, exposed mother compared with non-exposed mother, as seen in the article by Ystrom et al1. Confoundings beyond family history or indications of acetaminophen exist and are hard to be corrected. The increased risk might be due to maternal factors, e.g. sociodemographic status, chronic pain without documented diagnosis, that lead increased consumption of acetaminophen. Therefore, the title “prenatal exposure to acetaminophen and risk of ADHD” might cause unnecessary panic among expectant mothers, in which group the analgesic selection is already limited due to the concerns of risks.
References:
1. Ystrom E, Gustavson K, Brandlistuen RE, et al. Prenatal Exposure to Acetaminophen and Risk of ADHD. Pediatrics. October 2017:e20163840–11.
2. Clements CC, Castro VM, Blumenthal SR, et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry. 2015;20(6):727-734.
3. Sujan AC, Rickert ME, Öberg AS, et al. Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring. JAMA. 2017;317(15):1553–10.