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Original Investigation |

Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders

Zeyan Liew, MPH1; Beate Ritz, MD, PhD1,2; Cristina Rebordosa, MD, PhD3,4; Pei-Chen Lee, PhD1,5; Jørn Olsen, MD, PhD1,6
[+] Author Affiliations
1Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles
2Department of Neurology, School of Medicine, University of California, Los Angeles
3Arizona Respiratory Center, the BIO5 Institute, University of Arizona, Tucson
4Global Clinical Epidemiology, Drug Safety, and Epidemiology, Novartis Farmaceutica SA, Barcelona, Spain
5Department of Health Care Management, College of Healthcare Administration and Management, National Taipei University of Nursing Health Sciences, Taipei, Taiwan
6The Institute of Public Health, University of Aarhus, Aarhus, Denmark
JAMA Pediatr. 2014;168(4):313-320. doi:10.1001/jamapediatrics.2013.4914.
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Importance  Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development.

Objective  To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)–like behavioral problems or hyperkinetic disorders (HKDs) in children.

Design, Setting, and Participants  We studied 64 322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002.

Exposures  Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth.

Main Outcomes and Measures  To ascertain outcome information we used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. We estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen.

Results  More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < .001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother’s mental health problems, or other potential confounders we evaluated.

Conclusions and Relevance  Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed.

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Flowchart of Study Population Selection

ADHD indicates attention-deficit/hyperactivity disorder; DNBC, Danish National Birth Cohort; HKD, hyperkinetic disorder; SDQ, Strengths and Difficulties Questionnaire.

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