Updated: May 12, 2020
“The Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood”
Acetaminophen (branded version Tylenol) is often touted as the only safe pain reliever in pregnancy. Currently with the opioid epidemic, and doctors being more reticent to prescribe narcotics, acetaminophen’s use in pregnancy has likely increased. For instance, many newer surgical recovery algorithms, such as those used with cesareans, include the intravenous formula of acetaminophen. So when the article “The Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood” in JAMA Psychiatry demonstrates a dose-response association of acetaminophen biomarkers in stored umbilical cord blood from birth with attention deficit/hyperactivity disorder (ADHAD) and autism spectrum disorder (ASD), as an Ob/Gyn, I have to consider what this means for acetaminophen use in pregnancy.
First a bit about the paper, this is a remarkable endeavor with 996 participants: 257 with ADHD, 66 with ASD, 42 with both ADHD and ASD, 304 with other developmental disorders, and 327 with neurotypical development. All participants had enough stored umbilical cord blood from birth for testing, and follow-up care for approximately ten years. The authors calculated a “cord acetaminophen burden” by borrowing metabolite proportions from adult pathways. They then divided the participants into tertiles (or thirds) based on their calculated “cord acetaminophen burdens,” and compared the second and third tertiles, with the first tertile with respect to outcomes of ADHD and ASD to calculate odds ratios. The results are increased odds ratios for the second tertile of 2.26 for ADHD and 2.14 for ASD, and for the third tertile of 2.86 for ADHD and 3.62 for ASD. At first glance, these are rather high odds ratios; however, the ADHD and ASD groups had significantly more participants born prematurely and with low birth weights. Placentas of premature and small birth weight babies likely do not efficiently digest acetaminophen as do those from term or larger infants. Further, premature births often have some component of an inflammatory process, which might account for some of the acetaminophen use near birth. Lastly, the measured concentrations of acetaminophen and metabolites at the time of birth may or may not reflect the total use during pregnancy. Regardless, the study suggests an association of acetaminophen use in pregnancy with ADHD and ASD. A pediatrician commented on the JAMA website:
James Little, MD | Jackson Pediatrics
I'm just an old general pediatrician who has watched this subject for some time.
It has seem to me, for a long time, that the marked increase in the frequency of Autism Spectrum Disorders (and ADHD) could more readily be associated with the timing of the change from use of ASA to Acetaminophen with the recognition of the association of Reyes Syndrome with ASA use and the rapid discontinuation of ASA use that followed.
I understand the theory and timeline, and agree with the authors that further investigation is warranted.
As for pregnant women, I would still recommend using acetaminophen. I would certainly use acetaminophen to lower a fever, as a fever can harm a fetus. I think sporadic use for a moderate to severe ache or pain is appropriate, but maybe not for milder aches and pains, or any PM version to just get sleep.
Ji Y, Azuine RE, Zhang 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. Published online October 30, 2019. doi:https://doi.org/10.1001/jamapsychiatry.2019.3259