Acetaminophen (paracetamol) During Pregnancy May Alter Fetal Development

PainRelief.com Interview with:
Ann Z. Bauer ScD
Department of Work Environment
University of Massachusetts Lowell | UML 

PainRelief.com:  What is the background for this study?  What are the main findings of the underlying studies?

Response: Acetaminophen (paracetamol, brand name Tylenol) is an over-the-counter medication used to relieve pain and reduce fever. It is an active ingredient in over 600 medications and used by more than 50% of pregnant women worldwide and up to 65% of pregnant women in the US.

Current guidance recommends acetaminophen as the pain reliever of choice during pregnancy, as other pain relievers such as ibuprofen and aspirin are contraindicated during pregnancy, particularly after 20 weeks.

In this consensus statement the authors reviewed the research on acetaminophen use during pregnancy from 1995 through 2020 and found a growing body of evidence that suggests prenatal acetaminophen exposure may alter fetal development increasing the risk of neurodevelopmental, reproductive and urogenital disorders. Importantly, this review identifies a convergence of evidence from the trifecta of research areas -human cohort studies, in vitro and animal models. This statement asking for precaution and more research was supported by a total of 91 clinicians and researchers (13 authors and 78 signatories) from around the world.

Research suggests acetaminophen is an endocrine disruptor meaning it interferes with the proper functioning of hormones, specifically it is an anti-androgen that can significantly reduce testosterone production.  Acetaminophen exposure during pregnancy has been suggested to increase the risk of male undescended testicles (cryptorchidism) and shorter anogenital distance (ADG) a marker of sub-fertility.  Additionally, research suggests increased risk of neurodevelopmental disorders primarily attention deficit hyperactivity disorder (ADHD) and related behavioral abnormalities, but also autism spectrum disorder (ASD), language delays, decreased IQ, and conduct disorders.

Many users do not consider acetaminophen to be a medication with potential side effects. There is high usage, in part, because of a perception  that use is of negligible risk.  However, because use is so common, if acetaminophen is responsible for even a small increase in individual risk it could contribute substantially to these disorders in the overall population.

PainRelief.com: What should readers take away from your report?

Response: While we recognize that acetaminophen is an important medication and alternatives for treatment of high fever and severe pain are limited, based on our summary of this evidence, we call for precautionary action and recommend that pregnant women:

  • Forego acetaminophen use unless medically indicated.
  • Minimize risk by using the lowest effective acetaminophen dose for the shortest possible time.
  • Consult with their physician or pharmacist if uncertain whether use is indicated and before using on a long-term basis.

We also call for:

Education and acetaminophen-specific risk communication between health professionals and pregnant women so informed decisions can be made.

PainRelief.com: What recommendations do you have for future research as a result of this work?

Response: The statement calls for a focused research effort to investigate these impacts further.  Since it is unethical to do randomized controlled trials when an exposure is thought to be harmful, we must rely on human observational and experimental (in-vitro and in-vivo) studies.  Any scientific assessment of causation combines the knowledge from these laboratory and epidemiological studies. We would like to see human observational studies designed to accurately capture acetaminophen exposure and reason for use for both use by the mother during pregnancy and also the infant during the first years of life.  This perhaps could be done with a cell phone app with a daily ping asking 2 questions “Was acetaminophen used today?  What was it used for?” We would also like additional studies to better understand the hormonal, epigenetic  and metabolic mechanisms.

PainRelief.com: Is there anything else you would like to add?

Response: The risks from one-time use in most studies were modest.  However, most women reported repeated use and the majority of studies showed that risk increased with longer use and higher doses. The majority of  studies found associations regardless of the reason for use.

Across the studies, the majority of acetaminophen use during pregnancy was for discomfort -headache, back pain, girdle pain etc.  About 1/3 of use was for fever and infection, which left untreated have their own risks.  The better the tools used in the research, the stronger the signal that was found. When APAP exposure was measured using biological samples instead of maternal report of exposure, stronger effects were observed.

Again, the important take home message is, as a precaution until we know more, women should take acetaminophen only when medically indicated and at the lowest possible dose and for the shortest time possible. 

Citation:

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

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