Pain reliever use in pregnancy shows no link to child neurodevelopmental disorders, study finds

In a recent study published in the Journal of American Medical Association (JAMA), researchers assessed the association between acetaminophen use in pregnancy and the risk of intellectual disability, autism, and attention-deficit/hyperactivity disorder (ADHD) in children.

Acetaminophen is commonly used for pain and fever management during pregnancy. However, the European Medicines Agency and the United States (US) Food and Drug Administration consider that its use might pose a minimal risk in pregnancy. Further, a 2021 consensus statement from international clinicians and scientists recommended that pregnant individuals may forgo acetaminophen unless medically indicated due to the potential risk of developmental disorders.

Study: Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability. Image Credit: luchschenF / Shutterstock

About the study

In the present study, researchers investigated the use of acetaminophen in pregnancy and the risk of intellectual disability, ADHD, and autism in children. They included singleton children born in Sweden between July 1995 and December 2019. Unique identifiers assigned to residents at birth/emigration were used to link children and parents. Children were excluded if data on their parent’s birth country, age, household income/education, and region of residence were lacking.

Acetaminophen usage during pregnancy was identified from the Medical Birth Register. Information on early drug exposure was prospectively collected at the first antenatal visit, around 8–10 gestational weeks, during which midwives conducted examinations/interviews and recorded the use of prescription or over-the-counter medications. Later, the physician and midwife documented the use of medications.

From July 2005, the Medical Birth Register was supplemented with data from the Prescribed Drug Register, covering all prescription dispensations. The primary exposure was the ever-use of acetaminophen in pregnancy, ascertained from the Medical Birth and Prescribed Drug registers. A secondary exposure was the dose for a subsample with Prescribed Drug Register coverage.

The average daily dose of acetaminophen was estimated for each pregnancy. Diagnoses of intellectual disability, ADHD, and autism, identified from the National Patient Register, were the primary outcomes. Children were followed up until neurodevelopmental disorder diagnosis, emigration, death, or December 31, 2021. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals, accounting for the clustering of siblings by family.

Models were adjusted for covariates and the use of the following analgesics: aspirin, antimigraine medicines, non-aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids. Differences in absolute risk at 10 years were computed. Further, a sibling analysis was performed to account for unobserved environmental and genetic confounders shared between siblings, adjusted for all putative confounders.

Findings

Overall, the study included over 2.48 million children, of which 7.49% were exposed to acetaminophen in pregnancy. Drug exposure was more prevalent among children born to those with a higher body mass index (BMI) in early pregnancy, lower socioeconomic position, diagnoses of psychiatric conditions and neurodevelopmental disorders, and those who smoked during pregnancy.

During a median of 13.4 years of follow-up, 188,929 children had a diagnosis of at least one neurodevelopmental disorder. In total, 146,386 children had ADHD, 68,584 had autism, and 24,554 had intellectual disability. The median age at the diagnosis of autism, ADHD, and intellectual disability was 11.6, 12.2, and 8.2, respectively. Children exposed to acetaminophen had a slightly higher risk of ADHD, autism, and intellectual disability than those who were unexposed.

Differences in absolute risk at 10 years were slight. In models with sibling control, acetaminophen exposure was not associated with the risk of neurodevelopmental disorders. The magnitude of association between neurodevelopmental disorders and acetaminophen was similar to or lower than that for aspirin, opioids, antimigraine medications, and non-aspirin NSAIDs.

Of note, aspirin was inversely associated with neurodevelopmental disorders in sibling analyses, while there was a null association between antimigraine medicines, opioids, and non-aspirin NSAIDs and neurodevelopmental disorders. There was a dose-response association in partially adjusted models, which attenuated upon covariate adjustment and diminished in the sibling analysis.

Conclusions

Taken together, sibling control analyses revealed no associations between the use of acetaminophen in pregnancy and children’s risk of ADHD, intellectual disability, and autism. This suggested that the small, increased risk of these disorders associated with acetaminophen use in models without sibling control might be attributable to unmeasured confounding.

While a dose-response association pattern was observed, it was attenuated with increasing covariate control and nullified upon sibling control. Although acetaminophen was not associated with increased risk even with the highest dose, the researchers caution against interpreting it as a benchmark for safety.