In a recent consensus statement published in Nature, titled “Paracetamol use during pregnancy — a call for precautionary action,” thirteen researchers summarize data on the use of paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen, or under the most common brand name Tylenol) in pregnancy and its possible risks to offspring. They state intra-uterine exposure “might be associated with both reproductive and neurobehavioural abnormalities in both sexes.”1 The neurobehavioral data comes from well over twenty articles from nine countries including Norway, Denmark, the USA, Canada, New Zealand, the UK, Spain, Brazil, and Taiwan.2-24 The authors of this consensus statement authored most of the cited articles. To evaluate the claim whether acetaminophen is associated with neurobehavioral changes in children, this blog will review most of the articles in detail and look for other factors that might contribute to these changes. Some of these factors, or confounders, may seem overly probing, to shame pregnant mothers, or critical of children. There are many factors that are out of anyone’s control, but regarding controllable exposures, data on possible effects is warranted, although the research may be stigmatizing.
The studies on paracetamol in pregnancy, as reviewed in this consensus statement,1 often make it into the press as a possible cause for the increase in autism; however, only four of the articles address a possible association to autism. These include studies from Denmark and Spain and two from the USA.11,14,17,18 The article from Denmark linked exposure to autism with hyperactivity, but not to autism without hyperactivity.11 A maternal interview study from Spain showed only a weak association with autism, and mothers who recalled taking acetaminophen in pregnancy were more likely to be smokers, have a chronic illness, and have had fevers in pregnancy.14 Of the two studies from the USA, the first did not show that maternal blood levels of acetaminophen shortly after birth were associated with autism, but only with attention deficit hyperactivity disorder (ADHD). The second study showed that umbilical cord blood levels of acetaminophen and its metabolites were increased in children with both ADHD and autism, but in both US studies, affected children had lower birth weights and more prematurity.17,18 In general, given the same exposure to APAP, a smaller baby would be expected to have a higher blood level than a larger baby. Those articles are the only four listed addressing autism outcomes. All other studies of neurobehavioral outcomes in children born to women who took APAP during pregnancy only address ADHD,2,3,5,9,13,17-21,22,23 or childhood behavior or executive functioning.4,6,7,8,10,12,15 Of these nineteen articles, seventeen report positive findings of APAP and behavioral outcomes, while two articles report negative findings.16,22 Most rely on questionnaires or surveys of mothers,2-4,6-15,19,21,22,24 and many rehash differing outcomes from the same data sets of mothers.2,3,6-12 Mothers who answer yes to taking acetaminophen in pregnancy are more often smokers, have taken other medications, have a chronic illness, or had a fever, and/or inflammation during pregnancy.2-5,7-15,17,18 Seventeen articles list such confounders, while two articles do not investigate confounders.19,24 The authors of the consensus statement note that the “observational studies were limited by potential confounding, including by indication for APAP use, by genetic factors and by bias introduced by exposure and outcome misclassification, as well as study participant loss to follow-up.”1 Most articles only classify exposure during pregnancy or per trimester; only two Norwegian articles quantify the exposure in days of use as over 20 days or over 27 days of use during pregnancy, and both analyze the same data set of patients.7,20 To overcome the biases of recall and dose, a few articles employ different protocols. One from Norway demonstrates epigenetic changes by methylation of certain oxidative genes associated with ADHD in cord blood of infants with greater than 20 days of intrauterine exposure to APAP.20 Another, from Canada, shows a dose-dependent association of acetaminophen and its metabolites in meconium obtained at birth from children later diagnosed with ADHD at 7-8 years of age, and activity in the frontotemporal lobes of the brain by functional MRI at ages 9-10 years of age.23 These two articles may give more credence to the theory of neurodevelopmental changes seen after APAP exposure in the womb, but in the Norwegian study, the women also had more alcohol intake, depression, co-medication use, and infection. These confounders might also play a role in epigenetics. The Canadian study does not address other medications or maternal fevers, nor gives birth weights or information on prematurity, all of which might affect the metabolism of APAP and be linked to ADHD and MRI changes. Further, a similar study from the USA "did not find evidence of neurodevelopmental harm from prenatal exposure to acetaminophen measured in meconium.”16 Again, to be certain, except for the four articles listed at the beginning, these articles primarily address ADHD or hyperactivity, and not autism specifically.
So, what is the take-home message with all of this? There are two main points the authors make that are valid: The first is that we need better epidemiological studies on acetaminophen in humans that account for confounders, genetics, exposure, duration, indication, dosing, and outcomes. The second is that pregnant women may continue to take acetaminophen in pregnancy as needed, but not without a clear medical indication and at “the lowest effective APAP dose for the shortest possible time.”1
1. Bauer, A.Z., Swan, S.H., Kriebel, D. et al. Paracetamol use during pregnancy — a call for precautionary action. Nat Rev Endocrinol (2021). https://doi.org/10.1038/s41574-021-00553-7
2. Liew, Z., Bach, C. C., Asarnow, R. F., Ritz, B. & Olsen, J. Paracetamol use during pregnancy and attention and executive function in offspring at age 5 years. Int. J. Epidemiol. 45, 2009–2017 (2016).
3. Liew, Z., Ritz, B., Virk, J., Arah, O. A. & Olsen, J. Prenatal use of acetaminophen and child IQ: a Danish cohort study. Epidemiology 27, 912–918 (2016).
4. Rifas-Shiman, S. L. et al. Associations of prenatal or infant exposure to acetaminophen or ibuprofen with mid-childhood executive function and behaviour. Paediatr. Perinat. Epidemiol. 34, 287–298 (2020).
5. Leppert, B. et al. Association of maternal neurodevelopmental risk alleles with early-life exposures. JAMA Psychiatry 76, 834–842 (2019).
6. Tronnes, J. N., Wood, M., Lupattelli, A., Ystrom, E. & Nordeng, H. Prenatal paracetamol exposure and neurodevelopmental outcomes in preschool-aged children. Paediatr. Perinat. Epidemiol. 34, 247–256 (2020).
7. Brandlistuen, R. E., Ystrom, E., Nulman, I., Koren, G. & Nordeng, H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int. J. Epidemiol. 42, 1702–1713 (2013).
8. Vlenterie, R. et al. Neurodevelopmental problems at 18 months among children exposed to paracetamol in utero: a propensity score matched cohort study. Int. J. Epidemiol. 45, 1998–2008 (2016).
9. Ystrom, E. et al. Prenatal exposure to acetaminophen and risk of ADHD. Pediatrics 140, e20163840 (2017).
10. Liew, Z., Ritz, B., Rebordosa, C., Lee, P. C. & Olsen, J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr. 168, 313–320 (2014).
11. Liew, Z., Ritz, B., Virk, J. & Olsen, J. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: a Danish national birth cohort study. Autism Res. 9, 951–958 (2016).
12. Petersen, T. G. et al. Use of paracetamol, ibuprofen or aspirin in pregnancy and risk of cerebral palsy in the child. Int. J. Epidemiol. 47, 121–130 (2018).
13. Thompson, J. M. D., Waldie, K. E., Wall, C. R., Murphy, R. & Mitchell, E. A. Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years. PLoS ONE 9, e108210 (2014).
14. Avella-Garcia, C. B. et al. Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int. J. Epidemiol. 45, 1987–1996 (2016).
15. Stergiakouli, E., Thapar, A. & Davey Smith, G. Association of acetaminophen use during pregnancy with behavioral problems in childhood: evidence against confounding. JAMA Pediatr. 170, 964–970 (2016).
16. Laue, H. E. et al. Association between meconium acetaminophen and childhood neurocognitive development in GESTE, a Canadian cohort study. Toxicol. Sci. 167, 138–144 (2019).
17. Ji, Y. et al. Maternal biomarkers of acetaminophen use and offspring attention deficit hyperactivity disorder. Brain Sci. 8, 127 (2018).
18. Ji, Y. et al. 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 77, 180–189 (2020).
19. Tovo-Rodrigues, L. et al. Is intrauterine exposure to acetaminophen associated with emotional and hyperactivity problems during childhood? Findings from the 2004 Pelotas birth cohort. BMC Psychiatry 18, 368 (2018).
20. Gervin, K., Nordeng, H., Ystrom, E., Reichborn-Kjennerud, T. & Lyle, R. Long-term prenatal exposure to paracetamol is associated with DNA methylation differences in children diagnosed with ADHD. Clin. Epigenetics 9, 77 (2017).
21. Golding, J. et al. Associations between paracetamol (acetaminophen) intake between 18 and 32 weeks gestation and neurocognitive outcomes in the child: a longitudinal cohort study. Paediatr. Perinat. Epidemiol. 34, 257–266 (2020).
22. Tovo-Rodrigues, L. et al. Low neurodevelopmental performance and behavioural/emotional problems at 24 and 48 months in Brazilian children exposed to acetaminophen during foetal development. Paediatr. Perinat. Epidemiol. 34, 278–286 (2020).
23. Baker, B. H. et al. Association of prenatal acetaminophen exposure measured in meconium with risk of attention-deficit/hyperactivity disorder mediated by frontoparietal network brain connectivity. JAMA Pediatr. 174, 1073–1081 (2020).
24. Chen, M.-H. et al. Prenatal exposure to acetaminophen and the risk of attention-deficit/hyperactivity disorder: a nationwide study in Taiwan. J. Clin. Psychiatry 80, 18m12612 (2019).
