Expert Commentary
Does in utero exposure to valproate increase the risk of autism?
Yes.
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.
Related articles:
• How can pregnant women safely relieve low-back pain? Roselyn Jan W. Clemente-Fuentes, MD; Heather Pickett, DO; Misty Carney, MLIS; and Paul Crawford, MD (January 2014)
• Perinatal depression: What you can do to reduce its long-term effects. Janelle Yates (February 2014)
• Low-dose aspirin and preeclampsia prevention: Ready for prime time, but as a “re-run” or as a “new series”? John T. Repke, MD (Guest Editorial; June 2014)
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.
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, RPH, PhD; Aarienne Einarson, RN; and Teresa Baker, MD
WE WANT TO HEAR FROM YOU!
Share your thoughts on this article. Send your Letter to the Editor to: rbarbieri@frontlinemedcom.com
