New evidence reassures safety of acetaminophen use during pregnancy

A rigorous systematic review of the present state of knowledge on the use of acetaminophen during pregnancy and the risk of specific neurodevelopmental disorders (NDDs), such as autism and ADHD, offers reassurance that acetaminophen does not increase the risk of NDDs. The study in the Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP), published by Elsevier, points to methodological inadequacies in previous reviews and studies. It offers reassurance for pregnant women, public health agencies, and healthcare providers in alignment with recommendations from the Centers for Disease Control and Prevention (CDC), American College of Obstetricians and Gynecologists (ACOG), and The Society of Obstetricians and Gynecologists of Canada (SOGC).

Acetaminophen (paracetamol) is the most commonly used over-the-counter pain reliever during pregnancy, taken in an estimated 70% of all pregnancies. In 2021, a commentary about a possible increased risk of NDDs in children exposed to acetaminophen in utero was published, leading to substantial concerns in the general population and among prescribers. However, this publication—as well as a subsequent narrative review by the same group of researchers—was met with criticism of its methodology, choice and quality of studies considered, and lack of mechanistic data.

Acetaminophen exposure during pregnancy is difficult to assess in epidemiological studies because it is available over the counter without a prescription and is used as needed. Hence, there is inconsistency between studies regarding the risk of NDDs associated with its use in pregnancy.

Given the significant methodological challenges in this area, additional individual studies will inevitably suffer the same limitations as are already present in published studies. An integrative approach, summarizing the present state of knowledge and quantifying specific methodological areas of biases, as our study does, is needed in order to have a significant impact in future studies performed as well as on the causal effect of acetaminophen use during pregnancy on the risk of specific NDDs."

Anick Bérard, PhD, lead author of the current systematic review and meta-analysis, University of Montreal and CHU Sainte-Justine, Montréal, Quebec, Canada

Dr. Bérard and an international group of experts in the field conducted a comprehensive search of major bibliographic databases and grey literature to identify human studies evaluating the association between prenatal acetaminophen exposure and the risk of NDDs in offspring. Sixteen studies retrieved met eligibility criteria. In the resulting novel systematic review and meta-analysis, the investigators applied rigorous systematic review methodologies to determine the extent to which current data can support an association between prenatal exposure to acetaminophen and the risk of NDDs in children. They also used quantitative bias analysis to provide an estimate of the direction, magnitude, and uncertainty arising from systematic errors when assessing acetaminophen use during pregnancy and the risk of ADHD in children and performed sensitivity analyses.

Dr. Bérard notes that while a modest but significant association between acetaminophen use during pregnancy and ADHD in children was initially observed, concerns about its reliability remain. She explains, "This association is unlikely to be explained by possible confounding factors that were assessed but were not seen when sibling controls (considered to be the most reliable study design for assessing this risk) were used."

The authors conclude that the observed increase in ADHD risk is likely not causal and can be explained by inherent biases and underlying genetic factors. They recommend further studies to examine this association more robustly.

Commenting on the study, noted expert in the field David Coghill, MD, Financial Markets Foundation Chair of Developmental Mental Health in the Departments of Paediatrics and Psychiatry at the University of Melbourne, observes, "This is a landmark study that highlights the importance of good science and strong methods. The findings of no association between acetaminophen use during pregnancy and the risk of autism and ADHD in the child are not unexpected. These new findings support the position of professional organizations and regulatory bodies around the world that women should continue to use acetaminophen during pregnancy and do so without fear. The fact that they contradict the recent announcements by the US government must be acknowledged and acted on."