Another Study Finds No Ties Between Tylenol in Pregnancy and Autism

Positive associations between maternal acetaminophen prescriptions during pregnancy and attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring became null in sibling-matched analyses, a nationwide cohort study in Taiwan found.

In the full study cohort of more than 2 million births, offspring ADHD was linked with prenatal exposure to acetaminophen (HR 1.12, 95% CI 1.10-1.14), with a dose-response-like association for higher frequencies of medication use or higher mean daily dispensed doses, reported Pei-Chen Lee, PhD, of National Cheng Kung University in Taiwan, and colleagues.

ASD in children also was associated with prenatal exposure to acetaminophen (HR 1.06, 95% CI 1.03-1.09), but with effect estimates “smaller in magnitude,” they wrote in JAMA Pediatrics.

However, in sibling-matched analyses with more than 1.2 million kids having at least one sibling for comparison, associations between prenatal exposures to acetaminophen and ADHD and ASD among offspring became null, Lee’s group stated.

Nonetheless, in further analyses of sibling data, they found a positive association between prenatal exposure to acetaminophen and adverse neurodevelopmental outcomes when the older sibling was exposed (HR 1.33, 95% CI 1.17-1.52 for ADHD; HR 1.75, 95% CI 1.29-2.36 for ASD) and a negative association when only the younger sibling was exposed (HR 0.75, 95% CI 0.67-0.84 and HR 0.74, 95% CI 0.57-0.96, respectively).

“The substantial reversal of findings when assessing the outcome risks if the older or the younger sibling was prenatally exposed to acetaminophen suggests the presence of unaddressed sources of bias, preventing firm conclusions from being drawn using the sibling comparison design in our study,” they wrote.

Cynthia Gyamfi-Bannerman, MD, of the University of California San Diego Health and a past president of the Society for Maternal-Fetal Medicine (SMFM), acknowledged that there’s “still some unmeasured bias” in the study. However, she told MedPage Today, “at least the sibling analysis seemed to bring the findings to the null.”

The link between acetaminophen use in pregnancy and subsequent risk of neurodevelopmental disorders in offspring was driven into the national spotlight last year when the Trump administration told pregnant women to think twice about using the drug while pregnant, despite lack of a solid scientific basis for the claim. Subsequently, the American College of Obstetricians and Gynecologists and SMFM have affirmed the safety and benefit of acetaminophen use during pregnancy for pain and fever.

National studies in Sweden and Japan demonstrated that positive associations between acetaminophen exposure during pregnancy and neurodevelopmental outcomes in offspring did not persist when analyses were repeated in sibling comparisons, the researchers noted. This could be due to the sibling analysis controlling for confounding effects such as genetic and familial risks, they noted.

Other comprehensive studies have also shown no clear links between neurodevelopmental disorders and mom’s acetaminophen use during pregnancy, including a recent comprehensive review of existing evidence and another systematic review that also assessed sibling comparison studies.

“I think that it’s telling that all of these cohort studies, that are designed as well as they can be, don’t get to a causal relationship,” Gyamfi-Bannerman said.

Still, Lee and colleagues wrote that the reversal of findings when assessing siblings by birth order indicates a need for further study. “A sibling design that uses investigator-led and age-standardized outcome assessment may help address potential bias arising from changes in the medical diagnostic pattern in the registry,” they wrote.

The study included 2,092,926 singleton births between 2004 and 2015. Nearly half of the children were born to mothers who had at least two acetaminophen prescriptions during pregnancy, according to data extracted from the Taiwanese National Health Insurance Research Database. Overall, 0.01% of kids had ASD, and 0.06% had ADHD.

The main analysis examined at least two prescription records to increase the likelihood of medication intake, with the model assuming higher frequencies of acetaminophen use or a higher mean daily dispensed dose indicators of increased exposure, they noted.

Study limitations included the examination of maternal acetaminophen prescription records, which do not capture over-the-counter (OTC) use of the medication, Lee and colleagues stated. In Taiwan, acetaminophen is available by prescription or OTC at pharmacies, but not at convenience or grocery stores.