What do we know about the possible link between acetaminophen use during pregnancy and autism?

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Each week, approximately 23% of the adult U.S. population use a fever reducer and painkiller, such as Tylenol, which is the brand name for the drug acetaminophen, also known as paracetamol^[1].
This medication is also widely used during pregnancy, with an estimated 59% to 65% of pregnant women using acetaminophen-containing drugs at some point during pregnancy^[2,3]. However, social media posts, like this one by the Facebook page Autism Claim Center, claiming that acetaminophen during pregnancy is linked to the onset of autism spectrum disorder (ASD) in children went viral in July 2022.

As we report below, some scientific studies have suggested that this might be the case. However, these studies have important limitations, therefore data on the topic is still inconclusive. Currently, moderate use of acetaminophen during pregnancy, under medical supervision, is still considered safe.

In 2021, a consensus statement published by a group of scientists generated controversy as it expressed concerns over the use of acetaminophen by pregnant women^[4]. They cited scientific studies suggesting a higher incidence of ASD among children whose mothers used acetaminophen during pregnancy. Furthermore, two meta-analyses concluded that there is an association between acetaminophen and a higher risk of ASD^[5,6].

However, this claim was met with skepticism by other experts who criticized the strength of evidence that underpinned the 2021 consensus statement^[4]. In an email to Lead Stories, which published a fact-check on the claim, the U.S. Food and Drug Administration (FDA) said that the studies were “too limited to make any recommendations based on these studies at this time”. In 2019, the European Medicine Agency (EMA) considered that the available evidence on the matter to be “inconclusive”. The American College of Obstetricians and Gynecologists (ACOG) also arrived at a similar conclusion.

One of the limitations is that all the studies referenced in the consensus statement and the meta-analyses mentioned earlier are observational. In observational studies, researchers compare the onset of medical conditions over time between people who use the medication and those who don’t^[7,8]. This makes observational studies more likely to be affected by bias than double-blind, randomized controlled clinical trials^[9].

One example of bias in observational studies is that the exposure to acetaminophen isn’t controlled. Therefore, researchers are uncertain about how much acetaminophen individuals take.

Another important limitation is that observational studies make it very difficult to eliminate confounding factors. Confounding factors are variables that affect the outcome of an experiment, but aren’t the variables being studied in the experiment. If scientists don’t factor in the influence of confounding factors in their study, they may draw erroneous conclusions about causality.

For instance, people use acetaminophen to reduce fever or to alleviate pain. It’s possible that certain medical problems, which cause pain or fever in pregnant women, also increase the risk of ASD by themselves. Therefore, pregnant women with these medical problems are more likely to use acetaminophen, but it’s the medical problem that increases the risk of ASD, not acetaminophen itself.

The third limitation is that several studies relied on self-reporting of acetaminophen use. However, self reporting isn’t entirely reliable as people’s recollection of whether and how much they used acetaminophen may not be reliable^[7,8].

One study overcame this problem associated with self-reporting by measuring the amount of acetaminophen in umbilical cord blood collected before birth. They found that the risk of developing ASD was higher among children who had the highest levels of acetaminophen in the cord blood^[10].

However, several experts pointed out the study’s limitations. One of the study’s biggest limitations is the absence of a control group, that is, a group of pregnant women who didn’t use acetaminophen. Without a control group, it is difficult to determine whether the incidence of ASD is really due to acetaminophen or some other factor.

According to experts, another important limitation is that detecting acetaminophen in the umbilical blood cord indicates the use of painkillers at birth, but not throughout pregnancy. It is likely that the way painkillers are used in the few hours preceding labor doesn’t represent general acetaminophen use during pregnancy. Therefore the acetaminophen levels reported in that study may not accurately reflect the fetus’ exposure to the drug during development. Therefore, the levels may be irrelevant to the child’s risk of ASD.

In summary, some of the scientific evidence available so far suggests that acetaminophen use in pregnant women may be associated with ASD in children. But as we explained above, the studies that reported an association were limited in their design and methods, making the evidence less reliable, as ACOG and health authorities have pointed out.

Furthermore, it’s important to consider not just the risks, but also the benefits provided by acetaminophen.

Firstly, alternatives to acetaminophen for pain relief are non-steroidal anti-inflammatory drugs and opioids, both of which carry proven risks for pregnant women, unlike acetaminophen. Secondly, simply abstaining from medicine altogether isn’t feasible for pregnant women, as Salena Zanofi, an obstetrician-gynecologist at the Cleveland Clinic explained.

“When you’re pregnant, it’s riskier to have an untreated fever than it is to take acetaminophen”.

Between the inconclusive studies about the risks of acetaminophen and the proven risks of using other painkillers or leaving fever untreated, it thus appears that the benefits of using acetaminophen outweigh the risks.

Finally, even the authors of the “consensus statement” acknowledged that studies reporting an association between acetaminophen and ASD didn’t observe significant risks when the drug was used for a short amount of time^[4]. The Cleveland Clinic also concluded that a small amount of acetaminophen didn’t increase risks. As Zanofi explained:

“If you have a fever or if pain is disrupting your daily life during pregnancy, it’s OK to take acetaminophen occasionally, we just don’t want you taking acetaminophen every day or long-term”.

ACOG also considers acetaminophen to be safe when used “prudent[ly]”.

In other words, the evidence for an association between acetaminophen use during pregnancy and ASD risk is uncertain. Currently, ACOG considers acetaminophen to provide more benefits than risks to pregnant women and that it remains the safest approach to treating fever or pain during pregnancy. As with any medication, it should only be taken when needed, in moderation, and under medical supervision.

REFERENCES

• 1 – Kaufman et al. (2002) Recent Patterns of Medication Use in the Ambulatory Adult Population of the United States. Journal of the American Medical Association.
• 2 – Liew et al. (2016) Paracetamol use during pregnancy and attention and executive function in offspring at age 5 years. International Journal of Epidemiology.
• 3 – Werler et al. (2005) Use of over-the-counter medications during pregnancy. American Journal of Obstetrics and Gynecology.
• 4 – Bauer et al. (2021) Paracetamol use during pregnancy — a call for precautionary action. Nature review endocrinology.
• 5 – Masarwa et al. (2018) Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies. American Journal of Epidemiology.
• 6 – Alemany et al. (2021) 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. European Journal of Epidemiology.
• 7 – Liew et al. (2016) Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study. Autism Research.
• 8 – Avella-Garcia et al. (2016) Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. International Journal of Epidemiology.
• 9 – Hammer et al. (2009) Avoiding Bias in Observational Studies. Deutsches Ärzteblatt International.
• 10 – Li et al. (2020) Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood. JAMA Psychiatry.