Zeyan Liew1, Beate Ritz2, Cristina Rebordosa3, Pei-Chen Lee4, Jørn Olsen5. 1. Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles. 2. Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles2Department of Neurology, School of Medicine, University of California, Los Angeles. 3. Arizona Respiratory Center, the BIO5 Institute, University of Arizona, Tucson4Global Clinical Epidemiology, Drug Safety, and Epidemiology, Novartis Farmaceutica SA, Barcelona, Spain. 4. Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles5Department of Health Care Management, College of Healthcare Administration and Management, National Taipei University of Nursing Health Sciences, Taipei, T. 5. Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles6The Institute of Public Health, University of Aarhus, Aarhus, Denmark.
Abstract
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.
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.
Authors: Philip J Wiffen; Sheena Derry; R Andrew Moore; Ewan D McNicol; Rae F Bell; Daniel B Carr; Mairead McIntyre; Bee Wee Journal: Cochrane Database Syst Rev Date: 2017-07-12
Authors: Zeyan Liew; Marianthi-Anna Kioumourtzoglou; Andrea L Roberts; Éilis J O'Reilly; Alberto Ascherio; Marc G Weisskopf Journal: Am J Epidemiol Date: 2019-04-01 Impact factor: 4.897
Authors: Kristen A Johnson; Lindsey A Sjaarda; Sunni L Mumford; Rebecca A Garbose; Karen C Schliep; Donald Mattison; Neil J Perkins; Jean Wactawski-Wende; Enrique F Schisterman Journal: Pharmacoepidemiol Drug Saf Date: 2016-03-08 Impact factor: 2.890