Mental Health

Prenatal acetaminophen exposure may affect ADHD in childhood


Major finding: Children exposed prenatally to acetaminophen were at a greater risk of being diagnosed with hyperkinetic disorder, having ADHD-like behaviors, or being on an ADHD medication, an association that was increased with exposure during more than one trimester and with more weeks of exposure.

Data source: A large prospective study using the Danish National Birth Cohort data and other national health registries evaluated the association between the three outcomes, and maternal use of acetaminophen, based on information obtained from the mothers of more than 64,000 children.

Disclosures: The study was supported by the Danish Medical Research Council. One of the authors was at the University of Arizona, Tucson, when she was involved in the study, but now works at Novartis Farmaceutica SA, in Barcelona.

Prenatal exposure to acetaminophen was associated with a significantly increased risk of attention-deficit/hyperactivity–like behavioral problems, a hospital diagnosis of hyperkinetic disorder (HKD), or being on ADHD medications in children at age 7 years, based data from more than 60,000 children obtained from the national birth registry and other health registries in Denmark.

The study was published online on Feb. 24, in JAMA Pediatrics (doi:10.1001/jamapediatrics.2013.4914). The risk of ADHD-like behaviors in children at age 7 years increased by 13% among those whose mothers had used acetaminophen overall during pregnancy. When acetaminophen was used in the second and third trimesters, the risk increased by 44%, and when used during all three trimesters, the risk increased by 24%.

Courtesy: Cleveland Clinic

The associations with these three outcomes were greater when acetaminophen (paracetamol) was used in more than one trimester and with increasing frequency of use (more than 20 weeks during pregnancy). Because exposure to acetaminophen is common, “these associations might explain some of the increasing incidence in HKD/ADHD, but further studies are needed,” Zeyan Liew, MPH, and his coauthors concluded. Mr. Liew is with the department of epidemiology, Fielding School of Public Health, University of California, Los Angeles.

The prospective study included 64,322 live-born children and their mothers who were enrolled in the Danish National Birth Cohort during 1996-2002, and data from the national hospital, psychiatric and prescription registries. The mothers had participated in three interviews about acetaminophen use during pregnancy: at the 12th and 30th weeks of gestation, and 6 months after giving birth (28,254 women who had missed at least one of these interviews and their children were excluded).

A subgroup of approximately 41,000 women who had responded to a self-administered questionnaire (the Strengths and Difficulties Questionnaire), when their child was 7 years of age were used to evaluate ADHD-like behaviors; 55% of the women in this group had used acetaminophen at some point in their pregnancy. In the entire group of 64,322 mothers, 56% had used acetaminophen during pregnancy.

Data obtained by the investigators included parental reports of ADHD-like behaviors at age 7 years; a hospital diagnoses of HKD at or after 5 years; and use of ADHD medications, mostly Ritalin. The researchers adjusted for possible confounders, including birthweight; sex; maternal age at child’s birth; socioeconomic status; drug and alcohol use during pregnancy; mother’s self-reports of psychiatric illnesses and childhood behavioral problems; and diseases or conditions that may have prompted the mothers to have used acetaminophen.

The associations between the use of prenatal acetaminophen and the increased risks of HKD or using an ADHD medication also increased when acetaminophen was used during two or more trimesters, and a significant trend appeared with the increasing weeks of use: When used for 20 or more weeks, the risk for an diagnosis of HKD increased by 84% and the risk of having received an ADHD medication increased by 53%, the researchers noted. These results were similar “when restricting to mothers who did not report psychiatric illnesses or episodes of fever, inflammation, and infections during pregnancy,” they added.

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The risk of ADHD-like behaviors in children at age 7 years increased by 13% among those whose mothers had used acetaminophen overall during pregnancy. When acetaminophen was used in the second and third trimesters, the risk increased by 44%, and when used during all three trimesters, the risk increased by 24%. 

Referring to evidence from animal and human studies suggesting that acetaminophen may be an endocrine disruptor, the authors wrote: “Maternal hormones, such as sex hormones and thyroid hormones, play critical roles in regulating fetal brain development, and it is possible that acetaminophen may interrupt brain development by interfering with maternal hormones or via neurotoxicity, such as the induction of oxidative stress that can cause neuronal death.”

The study strengths included the availability of different endpoints to evaluate different levels of ADHD and the use of prospective data (interviews with the mothers). But the findings were limited by the inability to evaluate the effect of dosage or number of pills, because the mothers were not able to provide this information. Despite the adjustment for confounding variables, “the possibility of unmeasured residual confounding by indication for drug use, ADHD-related genetic factors, or coexposures to other medications cannot be dismissed,” the researchers said.

In an accompanying editorial, Miriam Cooper, MRCPsych, of the Institute of Psychological Medicine, Cardiff, Wales, and her associates wrote that while the study’s results are potentially important, “caution should be exercised in ascribing causation to statistical associations between prenatal risk factors and adverse outcomes” and the results “should not change practice.” However, the findings should be used as a basis for future research and “underline the importance of not taking a drug’s safety during pregnancy for granted” (doi:10.1001/jamapediatrics.2013.5292).

The study was supported by the Danish Medical Council. Neither the researchers nor the editorialists had relevant financial conflicts to disclose.

Be cautious in interpreting this cohortThere are quite a few problems with the interpretation of this cohort. Most importantly, there is potential bias by indication. For example, women who needed more acetaminophen might have had conditions that could cause the outcome, rather than the acetaminophen. In addition, the doses were not known and more than 20,000 cases were excluded for missing interviews. Therefore, it is possible that they had many more parents with ADHD, which is often a genetic condition. The acetaminophen users had more muscle and joint diseases, more infections, and more psychiatric disease-which can affect the results, independent of acetaminophen.

Dr. Gideon Koren is director of the Motherisk Program at the Hospital for Sick Children, Toronto, and professor of pediatrics, pharmacology, pharmacy, and medical genetics, at the University of Toronto. He has no relevant disclosures.

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