Acetaminophen Use During Pregnancy, Behavioral Problems, and Hyperkinetic Disorders

JAMA Pediatrics (Impact Factor: 5.73). 02/2014; DOI: 10.1001/jamapediatrics.2013.4914
Source: PubMed


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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Available from: Zeyan Liew, Sep 03, 2015
    • "However, there is some evidence that early prenatal exposure makes an impact on the development of the central nervous system (CNS) and neurotransmission. Manifestations of these changes in the form of an abnormal behavior are emerging later in adulthood(Liew et al., 2014; Rebordosa et al., 2008, 2009; Scialli et al., 2010).As a result of their research Brandlistuen et al. (2013) found that long-term use of paracetamol during pregnancy may increase the risk of an adverse effects on child development. They observed temperament problems, deterioration of behavior and psychomotor development in children at 3 years of age. "
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    ABSTRACT: The present study has examined the influence of the prenatal and early life administration of paracetamol on the level of neurotransmitters in the spinal cord of rat pups. The effect of the drug was evaluated in 2-month old Wistar male rats exposed to paracetamol in doses of 5 (P5, n=9) or 15 mg/kg (P15, n=9) p.o. during the prenatal period and after birth until the completion of the second month of life. A parallel control group received tap water (Con, n=9). In this study we have determined the level of monoamines, their metabolites and amino acids in the spinal cord of rats using high performance liquid chromatography (HPLC) in the second month of life. The present experiment demonstrates the action of paracetamol at the molecular level associated with significant modulation of neurotransmission in the spinal cord related to dopaminergic and noradrenergic systems. Simultaneously, paracetamol administration increases the content of an aspartic and glutamic acids in the spinal cord at a critical time during development.
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    • "). NA4AP is furthermore suspected to have detrimental effects on the neurodevelopment of the unborn child, resulting in hyperkinetic disorders in early childhood and school age (Liew et al. 2014; Thompson et al. 2014; Brandlistuen et al. 2014). NA4AP as the major metabolite of aniline was found in the mg/L range in urine samples of employees exposed to aniline air concentrations below 2 ppm (Lewalter and Korallus 1985; Deutsche Forschungsgemeinschaft 1993). "
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    ABSTRACT: Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC–MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7–68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5–6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14–0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4–72.1 % of the oral aniline dose. Elimination half-times were 3.4–4.3 h for N-acetyl-4-aminophenol, 4.1–5.5 h for the mercapturic acid conjugate, and 1.3–1.6 and 0.6–1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen.
    Archive für Toxikologie 08/2015; DOI:10.1007/s00204-015-1566-x · 5.98 Impact Factor
    • "Nevertheless some investigators have assumed that prenatal and early life-threatening intake of paracetamol may induce abnormalities in the immune system, with symptoms such as wheezing and asthma (Amberbir et al., 2014; Beasley et al., 2008; Becker and Schultz, 2010; Henderson and Shaheen, 2013; Tiegs et al., 2014). In addition, recent studies have shown that the drug can affect also development of the central nervous system (CNS) and presumably is responsible for some behavioural disturbances in adulthood (Blaser and Allan, 2014; Liew et al., 2014). "
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    ABSTRACT: The effect and safety of prenatal and early life administration of paracetamol - routinely used over-the-counter antipyretic and analgesic medication on monoamines content and balance of amino acids in the medulla oblongata is still unknown. In this study we have determined the level of neurotransmitters in this structure in two-month old Wistar male rats exposed to paracetamol in the dose of 5 (P5, n=10) or 15mg/kg b.w. (P15, n=10) during prenatal period, lactation and till the end of the second month of life. Control group received drinking water (Con, n=10). Monoamines, their metabolites and amino acids concentration in medulla oblongata of rats were determined using high performance liquid chromatography (HPLC) in 60 postnatal day (PND60). This experiment shows that prenatal and early life paracetamol exposure modulates neurotransmission associated with serotonergic, noradrenergic and dopaminergic system in medulla oblongata. Reduction of alanine and taurine levels has also been established. Copyright © 2015 Elsevier B.V. All rights reserved.
    07/2015; 40(2):369-374. DOI:10.1016/j.etap.2015.07.001
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