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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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Comparison of the characteristics of women with or without acetaminophen use in pregnancy
Posted on March 4, 2014
Yona Amitai MD, MPH
Bar Ilan University, Ramat Gan, Israel
Conflict of Interest: Prof. Yona Amitai is a payed consultant for Teva Pharmaceuticals Industry Ltd. Israel, producer os acetaminophen formulations
March 4, 2014EditorJAMA PediatricsRe: Comment on the manuscript: Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders, by Liew et alDear Editor, The recent report on association between acetaminophen use in pregnancy with ADHD in childhood1, may bear practical implications for antipyretic use in pregnancy. Since hyperpyrexia in pregnancy has potential adverse effects including congenital malformations, the role of antipyretic medication in pregnancy is crucial. Numerous studies have shown associations between maternal hyperthermia and increased risk for neural tube defects in offspring2,3. Other have found associations between maternal fever and congenital heart defects (CHDs)4,5. Significant associations were found between fever and influenza and specific CHDs, including atrioventricular septal defects in infants with Down syndrome. Maternal antipyretic use in the setting of fever or influenza tended to decrease these associations5. In Liew's report, acetaminophen has been used by 56% of their study population1. The use of ibuprofen and aspirin in this cohort has been reported by others to be 10 fold and 7 fold lower respectively, compared with acetaminophen6. Since smoking, psychiatric illness, fever, infection and other risk factors may be significant risk factors for adverse pregnancy outcome, including ADHD, the detailed report of their occurrence in such a study is important. The report of these characteristics in Table 1 in this study is misleading. The authors compare the frequency of these variables between mothers who have used acetaminophen in pregnancy, with that of the whole group, rather than a direct comparison between those who used or did not use acetaminophen. Such comparison markedly attenuates the differences, since women who used acetaminophen were over half of the whole study population, and they were found to have higher frequency in most of the potential risk factors. Calculation of the frequency of some of these characteristics, based on the reported numbers of patients in their report, illustrate the marked differences between the 2 modes of comparison (Table). For example, the difference in the frequency of fever rose from 28.7% in the whole group and 33.4% in acetaminophen users to 22.7% and 33.4%, respectively (47% higher). Some of these differences are probably statistically (and clinically) significant. Although the differences in ADHD variables remained significant after adjusting for these confounders, the direct comparison of these confounders between acetaminophen users and non-users should be reported, with the p values of the differences. Table 1 Revised with direct comparison between mothers with or without APAP use in pregnancy in the Danish Birth Cohort (selected variables, calculated) Word count: 498 (including table)Yona Amitai, MD, MPHDepartment of Management, Public Health and Health management systemsBar Ilan University52900 Ramat Gan IsraelConflict of Interest: Prof. Amitai is a paid consultant for Teva Pharmaceuticals Ltd, Israel, producer of acetaminophen formulations.Comment:I have prepared a Table, but if I add it as a word file the figures are messed up, please allow me to submit the Table as PDF or in another wayYona AmitaiReferences:1. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders. JAMA Pediatr. 2014 Feb 24.2. Suarez L1, Felkner M, Hendricks K. The effect of fever, febrile illnesses, and heat exposures on the risk of neural tube defects in a Texas-Mexico border population. Birth Defects Res A Clin Mol Teratol. 2004; 70: 815-9.3. Moretti ME1, Bar-Oz B, Fried S, Koren G. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiology. 2005; 16: 216-9.4. Botto LD1, Lynberg MC, Erickson JD. Congenital heart defects, maternal febrile illness, and multivitamin use: a population-based study. Epidemiology. 2001; 12:485-90.5. Oster ME1, Riehle-Colarusso T, Alverson CJ, Correa A. Associations between maternal fever and influenza and congenital heart defects. J Pediatr. 2011; 158: 990-5. 6. Jensen MS, Rebordosa C, Thulstrup AM, Toft G, Sørensen HT, Bonde JP, Henriksen TB, Olsen J. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology. 2010; 21: 779-85
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