Researchers at the Barcelona Institute for Global Health (ISGlobal) have carried out an epidemiological study that they claim addresses some weaknesses of previous, similar studies, and supports a proposed link between maternal use of paracetamol (acetaminophen) during pregnancy, and symptoms of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum conditions (ASC) in their children. The newly reported study, which included more than 70,000 children in six European cohorts, found that children exposed to paracetamol before birth were 19% more likely to develop ASC symptoms and 21% more likely to develop ADHD symptoms than those who were not exposed.

“Our results address some of the weaknesses of previous meta-analyses,” commented Jordi Sunyer, PhD, researcher at ISGlobal and co-author of the team’s published paper in the European Journal of Epidemiology. “Considering all the evidence on the use of paracetamol and neurological development, we agree with previous recommendations indicating that while paracetamol should not be suppressed in pregnant women or children, it should be used only when necessary.”

The paper is titled, “Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention‑deficit and hyperactivity symptoms in childhood: Meta‑analysis in six European population‑based cohorts.”

At some point during pregnancy, an estimated 46-56% of pregnant women in developed countries use paracetamol, which is considered the safest analgesic/antipyretic for pregnant women and children. However, mounting evidence has linked prenatal paracetamol exposure to poorer cognitive performance, more behavioral problems, and ASC and ADHD symptoms, the authors noted.

Previous meta-analyses investigating the link between prenatal paracetamol use and ASC and ADHD symptoms have been criticized for their heterogeneity with respect to methods and instruments used to assess outcomes, statistical approaches and confounders. “Furthermore, these studies did not address relevant unsolved questions regarding the link between early acetaminophen exposure and ASC and ADHD symptoms,” the team wrote.

The newly reported study aimed to address weaknesses in previous research. “An effort was made to harmonize the assessment of ADHD and ASC symptoms and the definition of paracetamol exposure,” explained ISGlobal researcher and lead study author Sílvia Alemany, PhD. The study included data from six European population-based birth cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), DNBC, Gene and Environment: Prospective Study on Infancy in Italy (GASPII), the Generation R Study, INMA (including four subcohorts), and the Mother–Child Cohort in Crete (RHEA). Mother–child pairs were recruited from 1991 through 2008.

“The sample is large, and it includes cohorts from multiple European countries: the United Kingdom, Denmark, the Netherlands, Italy, Greece and Spain,” said Alemany. “We also used the same criteria for all of the cohorts, thereby reducing the heterogeneity of criteria that has hampered previous studies.”

In total, the researchers analyzed 73,881 children for whom data were available on prenatal or postnatal exposure to paracetamol, at least one symptom of ASC or ADHD, and main covariates. Depending on the cohort, 14% to 56% of the mothers reported taking paracetamol while pregnant. The results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have ASC and ADHD symptoms with in the borderline/clinical range , respectively, when compared with non-exposed children, the authors reported.

The link was only slightly stronger for boys. “When stratifying by sex, these associations were slightly stronger among boys compared to girls but positive associations with effect sizes of similar magnitude were observed in both strata, especially in the case of ADHD,” the team noted. “Our findings suggest that differential sex effects of acetaminophen on ASC and ADHD symptoms, if any, are modest and may be dependent on the number of cases, outcome definition and assessment.” Alemany added, “We also found that prenatal exposure to paracetamol affects boys and girls in a similar way, as we observed practically no differences.”

The most consistent pattern of results was observed for the association between prenatal acetaminophen exposure and ADHD symptoms, the team added. “The positive associations were observed in all the cohorts and of similar magnitude regardless of the cohort excluded in the leave-one-out analysis. This finding is in agreement with previous meta-analysis which reported likelihood increases of 25% and 34% for ADHD in relation to prenatal acetaminophen exposure.” The association between prenatal acetaminophen use and ASC symptoms was also consistently positive, even after omitting the largest cohort.

The study also analyzed postnatal exposure to paracetamol and found no association between paracetamol use during childhood and ASC symptoms. Nevertheless, the research team concluded that further studies are needed, given the heterogeneity of postnatal paracetamol exposure among the various cohorts, which ranged from 6–92.8%.

Acknowledging limitations of the reported research, the investigators nevertheless concluded that “… the homogeneity of the findings among the different cohorts, the novel assessment of postnatal acetaminophen exposure, and the use of an harmonized definition of exposure and outcome as well as of common statistical approaches overcomes the criticisms of previous meta-analysis.”

The team concluded, “These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.” They say that when considering all evidence on the use of paracetamol and neurodevelopment, they agree with previous recommendations suggesting that “ … although paracetamol should not be suppressed in pregnant women or children, it should be used only when necessary.”

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