Reference: JAMA. 2024 Apr 9;331(14):1205-1214
Practice Point: It is very unlikely that acetaminophen use during pregnancy causes autism, ADHD, or intellectual disability in offspring.
EBM Pearl: Finding an association in a cohort study may be more a signal to investigate further than a reason to change management.
When new evidence results in a shift in management for a particular condition, the concept of a swinging pendulum is often used to explain to patients how it’s really the body of evidence that’s growing, not that we keep changing our minds. Take the case of acetaminophen use during pregnancy. For many years, we said that acetaminophen was perfectly safe in pregnancy. Then starting around 2017, cohort data suggested an association with ADHD, autism, and developmental disorders in children exposed to acetaminophen during gestation. Interestingly, it seems more pregnant patients got wind of that news than did providers (cue the delay for evidence to be put into practice). But now, authors of another cohort study just published in JAMA found no such association and conclude the previous findings were due to confounding. No wonder patients are confused and somewhat distrusting.
This most recent cohort prospectively enrolled nearly 2.5 million singleton liveborn children born in Sweden from 1995 to 2019. Investigators collected information from national registries about birthing parents as well as their offspring using a unique identifier so they could couple gestational parents with their offspring and the offspring (siblings) with each other. Information included over-the-counter (OTC) and prescription use of acetaminophen, dosing, and information about the birthing parent’s medical diagnoses of migraine, chronic pain, infection, fever, rheumatoid arthritis, and headaches from a year before pregnancy until delivery. Reasons for OTC use that did not require medical attention were not captured. ICD codes for autism, ADHD, and intellectual disability in offspring were the primary outcome.
According to this study, about 7.5% of children were exposed to acetaminophen during gestation. This seems low, and is a lower proportion than that found in some other studies. However, the authors did simulations and statistically claim that even if acetaminophen exposure was under-ascertained, it wouldn’t have changed the results. Acetaminophen exposure occurred more often in birthing parents with lower socioeconomic status, higher BMI, those who smoked during pregnancy, had any psychiatric or neurodevelopmental conditions, and those who had indications for acetaminophen. About 7.6% of included children were diagnosed with at least one neuropsychiatric condition, specifically autism, ADHD, or intellectual disability.
In the population-based sample (all data), small but significant associations were found between any acetaminophen exposure during gestation and autism, ADHD, and intellectual disability, similar to the previous cohort data. However, the absolute differences were incredibly small. Further, and very importantly, no significant associations were found in a sibling-control analysis. The sibling-control cohort controlled for factors such as a birthing parent’s socioeconomic status, genetic predispositions, BMI, smoking status, or other potential unnamed confounders. Removing these confounders removed the significant difference between groups, which suggests that the causal link is not acetaminophen, but likely one or a combination of those other factors.
So how do we weave these data together in a tapestry that keeps pregnant patients (and ourselves) warm at night? The body of evidence is indeed growing, but there are growing pains. We started by looking for fetal harms through retrospective observational analyses and didn’t find any—that’s how acetaminophen got the now-retired pregnancy category A. Then the cohort studies started coming that did identify an association between acetaminophen use in pregnancy and autism, ADHD, and intellectual disability. The trouble is that the vast majority of consumers of this information took it as a causal association. What this most recent sibling-matched analysis tells us is that the previous studies actually did get it mostly right—there is an association, but it’s likely not between acetaminophen and these neuropsychiatric conditions. Rather, it’s the underlying reasons for taking acetaminophen that are associated with autism, ADHD, and intellectual disability. And that’s what we can tell our patients—not that the pendulum swung or that we changed our minds about whether acetaminophen is safe in pregnancy, but that investigators followed the trail of evidence and each time got us closer to the “truth.”
For more information, see the topic Medication and Drug Exposure in Pregnancy in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.