December 7, 2016

Acetaminophen and Risk of Behavioral Problems in Children

Prenatal use increases risk of ADHD symptoms
Associations between prenatal use of acetaminophen and behavioral problems in children adds to concerns about the safety of what is widely considered to be a benign over-the-counter remedy for pain and fever.


Stergiakouli E, Thapar A, Davey Smith GD. Association of acetaminophen use during pregnancy with behavioral problems in childhood: evidence against confounding. JAMA Pediatr. 2016;170(10):964-970.


Retrospective analysis of a prospective birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC)


Investigators collected and analyzed data from 7,796 mothers who were enrolled in the ALSPAC between April 1991 and December 1992. Data included information on the mothers’ children and partners.

Study Objective

To determine if association exists between child behavioral issues and acetaminophen use by the mother, or her partner, during or after pregnancy

Outcome Measures

Participants in the ALSPAC study completed a questionnaire regarding acetaminophen (paracetamol; brand name Tylenol) use at 18 and 32 weeks of pregnancy and then again when the child was 61 months old. When the children turned 7 years of age, maternal reports of behavioral problems using the Strengths and Difficulties Questionnaire (SDQ) were collected and evaluated. The SDQ contains 5 domains: emotional symptoms, conduct problems, hyperactivity symptoms, peer relationship problems, and pro-social behaviors.

Key Findings

Of the 7,796 mothers enrolled, 53% reported using acetaminophen at 18 weeks and 42% used it at 32 weeks. Prenatal acetaminophen use at 18 and 32 weeks of pregnancy was associated with a 20% higher odds of the child having conduct problems (risk ratio [RR]: 1.20; 95% confidence interval [CI]: 1.06-1.37) and a 23% higher odds of hyperactivity symptoms (RR: 1.23; 95% CI: 1.08-1.39). Maternal acetaminophen use at 32 weeks was associated with a 29% higher odds of the child having emotional symptoms (RR: 1.29; 95% CI: 1.09-1.53), 42% higher odds of conduct problems (RR: 1.42; 95% CI: 1.25-1.62), 31% higher odds of hyperactivity symptoms (RR: 1.31; 95% CI: 1.16-1.49), and 46% higher odds of total difficulties (RR: 1.46; 95% CI: 1.21-1.77) per the SDQ. The absolute percentage of children with behavioral issues, defined by the “total difficulties” domain on the SDQ, was 5%.
There was no association between maternal postnatal acetaminophen use or partner’s acetaminophen use and behavioral scores on the SDQ.
The researchers conclude: “Children exposed to acetaminophen prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner's acetaminophen use.”

Practice Implications

This latest study is consistent with previous research showing an association between acetaminophen use during pregnancy and the development of attention deficit hyperactivity disorder (ADHD) symptoms in the offspring.1-3
This new data adds to the growing body of research illustrating the many dangers of this commonly used over-the-counter (OTC) drug. It is widely understood that acetaminophen can damage the liver. In fact, it is the leading cause of acute liver failure in the United States and the United Kingdom.4,5 Acetaminophen reduces the liver’s store of the important detoxifying aid and antioxidant glutathione.6,7 Given the increased demands on the liver during pregnancy, this latest study further confirms that it is unwise for pregnant women to use it.
Even after birth, use of acetaminophen can be problematic for the child. Acetaminophen is often the drug of choice to relieve fever in children. However, use for fever in the first year of life is associated with an increase in the incidence of asthma and other allergic symptoms later in childhood.8 Asthma is another disease process that is influenced greatly by antioxidant mechanisms.8 Because acetaminophen severely depletes glutathione levels not only in the liver, but other tissues as well, it should not be used in children with asthma.9
This new data adds to the growing body of research illustrating the many dangers of this commonly used over-the-counter (OTC) drug.
The previous research combined with this latest study makes it clear that clinicians should caution patients about the dangers associated with acetaminophen use, especially in certain populations such as pregnant women and children. The studies suggesting increased risk of ADHD symptoms in children of mothers who take the drug during pregnancy should be highlighted in clinical practice.
According to the Centers for Disease Control and Prevention, the number of ADHD cases has increased significantly from 7.8% in 2003 to 11% in 2011.10 Attention deficit hyperactivity disorder can be an extremely challenging diagnosis for both child and parent. Anything that clinicians can do to reduce the number of children with this diagnosis will certainly lead to improved quality of life for their patients. Counseling pregnant mothers regarding alternatives to acetaminophen is a step in the right direction.
One natural substance that is a viable alternative for pregnant women is ginger (Zingiber officinale). Several double-blind studies have shown the benefits of ginger in a variety of gastrointestinal issues, especially those related to nausea and vomiting, including severe morning sickness.11 In addition, dozens of clinical studies have supported its use for reducing pain and inflammation in various forms of arthritis, chronic low back pain, muscle pain, and painful menstruation.12,13
It’s unfortunate that acetaminophen has become such a popular OTC drug given its adverse effects. In 2013 alone, adult Tylenol sales exceeded $200 million and Children’s Tylenol (liquid) rose to more than $51 million in sales.14 While people have become somewhat programmed to reach for acetaminophen when they experience an ache or pain, it’s up to physicians to inform them of the risks associated with its use, especially among pregnant women and their offspring.

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  1. Thompson JM, Waldie KE, Wall CR, Murphy R, Mitchell EA; ABC study group. Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years. PLoS One. 2014;9(9):e108210.
  2. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 2014;168(4):313-320.
  3. Hoover RM, Hayes VA, Erramouspe J. Association between prenatal acetaminophen exposure and future risk of attention deficit/hyperactivity disorder in children. Ann Pharmacother. 2015;49(12):1357-1361.
  4. Fontana RJ. Acute liver failure including acetaminophen overdose. Med Clin North Am. 2008;92(4):761-794.
  5. Lancaster EM, Hiatt JR, Zarrinpar A. Acetaminophen hepatotoxicity: an updated review. Arch Toxicol. 2015;89(2):193-199.
  6. National Institute of Diabetes and Digestive and Kidney Diseases. Acetaminophen. Accessed December 7, 2016. 12/7/16.
  7. da Rosa E, da Silva M, Carvalho N, et al. Reduction of acute hepatic damage induced by acetaminophen after treatment with diphenyl diselenide in mice. Toxicol Pathol. 2012;40(4):605-613.
  8. McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics. 2011;128(6):1181-1185.
  9. Sordillo JE, Scirica CV, Rifas-Shiman SL, et al. Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze in asthma in children. J Allergy Clin Immunol. 2015;135(2):441-448.
  10. Division of Human Development and Disability, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC). Attention-Deficit/Hyperactivity Disorder (ADHD). CDC web site: Updated October 5, 2016. Accessed November 14, 2016.
  11. Thomson M, Corbin R, Leung L. Effects of ginger for nausea and vomiting in early pregnancy: a meta-analysis. J Am Board Family Med. 2014;27(1):115-122.
  12. Aryaeian N, Tavakkoli H. Ginger and its effects on inflammatory diseases. Adv Food Technol Nutr Sci Open J. 2015;1(4):97-101.
  13. Mashhadi NS, Ghiasvand R, Gholamreza A, et al. Anti-oxidative and anti-inflammatory effects of ginger in health and physical activity: review of current evidence. Int J Prev Med. 2013;4(Suppl 1):S36-S42.
  14. Statista. Top OTC brands for pain relief by revenue in the US in 2013.