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Does prenatal acetaminophen exposure increase the risk of behavioral problems in the child?

Maybe. According to this cohort study from Denmark involving 64,322 live-born children and mothers, more than 50% of all mothers reported using acetaminophen while pregnant. Their children were at higher risk of receiving a hospital diagnosis of hyperkinetic disorder (HKD) (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.19-1.59), use of a medication for attention deficit/hyperactivity disorder (ADHD) (HR, 1.29; 95% CI, 1.151.44), or having ADHD-like behaviors at age 7 years (risk ratio, 1.13; 95% CI, 1.01-1.27).

In the continuing drive to determine the cause of neurobehavioral complications, particularly ADHD and HKD, a number of studies have reported associations with various substances. These include pesticides, (1) hormones, (2) hormone disrupters, (1) and, possibly, genetics. Nevertheless, the etiology of these disorders remains a mystery. ADHD is a complex and heterogeneous disorder. Although we do not yet understand the cause, genetics (or, more accurately, pharmacogenetics) seems likely to play a role.

This study from a large Danish population appears to suggest that the prenatal use of acetaminophen may increase the risk of ADHD and HKD. It is yet another study in which the data indicate and the authors claim that use of a particular drug during pregnancy is responsible for this condition. However, despite the extremely large sample size (which increases the likelihood of positive findings), the hazard ratios were only marginally significant, suggesting that the relevance of the conclusions is questionable.

Details of the study

The 64,322 live-born children and mothers in the Danish National Birth Cohort from 1996 to 2002 were evaluated three ways:

* through parental reports of behavioral problems in children at age 7 using the Strengths and Difficulties Questionnaire

* through retrieval of HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011

* through prescriptions for ADHD (primarily methylphenidate [Ritalin]) for children from the Danish Prescription Registry.

Liew and colleagues then estimated hazard ratios for receiving a diagnosis of HKD or using a medication for ADHD, as well as risk ratios for behavioral problems in children after prenatal exposure to acetaminophen.

Stronger associations between prenatal acetaminophen use and HKD or ADHD were found when the mother used the medication in more than one trimester. Exposure-response trends increased with the frequency of acetaminophen use during pregnancy for all three outcomes (HKD diagnosis, ADHD-like behaviors, and ADHD medication use; P trend <.001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, or the mother's mental health status.

Why these findings are less than compelling

Acetaminophen is the most commonly used medication during pregnancy, although few investigators have analyzed neurobehavioral complications in children exposed to this drug in utero. Another recent epidemiologic study from Norway also suggests that long-term exposure (>28 days) to acetaminophen increases the risk of poor gross motor functioning, poor communication skills, and externalizing and internalizing behavior problems. (3)

The rationale behind an association between acetaminophen and ADHD and HKD is that the medication is an endocrine-disrupting agent. The evidence of this status comes primarily from in vitro experiments from one group of researchers, which may not represent in vivo conditions. (4,5)

Epidemiologic studies frequently are confounded by poor design and methodology. It also should be noted that correlation is not necessarily the same as causation. In this study, the design and methodology were appropriate considering the data available. Researchers often use large databases like this to research "hot topics" such as the association between ADHD and prenatal acetaminophen use. In this study, acetaminophen cannot be associated definitively with an increased risk of ADHD or HKD. Further research is needed, with greater attention to possible confounding factors, such as why these women consumed chronic doses and for what conditions.

References

(1.) Kajta M, Wojtowicz AK. Impact of endocrine-disrupting chemicals on neural development and the onset of neurological disorders. Pharmacol Rep. 2013;65(6):1632-1639.

(2.) de Bruin El, Verheij F, Wiegman T, Ferdinand RF. Differences in finger length ratio between males with autism, pervasive developmental disorder-not otherwise specified, ADHD, and anxiety disorders. Dev Med Child Neurol. 2006;48(12):962-965.

(3.) Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: A sibling-controlled cohort study. Int J Epidemiol. 2013;42(6):1702-1713.

(4.) Kristensen DM, Lesne L, Le Fol V, et al. Paracetamol (acetaminophen), aspirin (acetylsalicylic acid), and indomethacin are anti-androgenic in the rat foetal testis. Int I Androl. 2012;35(3):377-384.

(5.) Albert O, Desdoits-Lethimonier C, Lesne L, et al. Paracetamol, aspirin, and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Hum Reprod. 2013;28(7):1890-1898.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

For the time being, you should probably counsel your patients to use acetaminophen sparingly during pregnancy, and certainly not on a daily basis. We also should encourage nonpharmacologic pain management, such as cognitive behavioral therapy, when appropriate, and caution patients against long-term use of analgesics, when possible, during gestation and lactation.

THOMAS W. HALE, PHD

ADRIENNE EINARSON, RN

TERESA BAKER, MD

> EXPERT COMMENTARY

>> Thomas W. Hale, PhD, Professor, Infant Risk Center, Texas Tech University School of Medicine; Adrienne Elnarson, RN, Infant Risk Center, Texas Tech University School of Medicine; and Teresa Baker, MD, Assistant Professor, Department of Obstetrics and Gynecology, Infant Risk Center, Texas Tech University School of Medicine, Amarillo, Texas.

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.

The authors report no financial relationships relevant to this article.
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Title Annotation:Examining the EVIDENCE
Author:Hale, Thomas W.; Einarson, Adrienne; Baker, Teresa
Publication:OBG Management
Date:Jul 1, 2014
Words:926
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