A Consensus Statement supported by 91 scientists, clinicians, and public health professionals published on September 23, 2021, calls for increased awareness of the risks of neurodevelopmental, reproductive, and urogenital disorders with acetaminophen (APAP) use during pregnancy in parents and healthcare professionals (3). Their statement recommends,
"that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time" (3).
Multiple studies published in the last 5 years and earlier have found several risks related to acetaminophen also known as paracetamol, use during pregnancy. Acetaminophen is the active ingredient in Tylenol and over 600 other medications, many of which can be purchased over-the-counter (OTC) intended to reduce fever or relieve pain (3). California added acetaminophen to the list of drugs "under consideration" to be added to the known carcinogens list in accordance with Prop 65 due to the risks reported in peer-reviewed studies in September 2019 (5). Many studies in both humans and rodents explore document and confirm the risks associated with acetaminophen during pregnancy. Despite this fact, many OBGYNs and other types of healthcare providers continue to recommend this medication as safe for use during pregnancy without warning about any potential adverse risks. I am unsure if they are just unaware of the evidence or if they dismiss the risks as less risk than the benefit.
In the hierarchy of evidence of research, the highest quality tier is the Meta-Analysis. A recent Meta-Analysis published in May of 2021 evaluated six European population-based cohorts including over 70,000 children to examine the association between acetaminophen exposure and neurodevelopmental diagnoses such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Conditions (ASC) symptoms and diagnosis. The results showed children prenatally exposed to acetaminophen were 19% and 21% more likely to have ASC and ADHD symptoms within the borderline/clinical range compared with non-exposed children (1). A smaller cohort study conducted in 2020 of 996 mother-infant pairs from the Boston Birth Cohort found that fetal exposure to acetaminophen was associated with a significant increase in the risk of childhood ASC and ADHD using fetal cord plasma biomarkers (8). Another 2020 cohort study of 345 children found that “acetaminophen exposure detected in meconium was associated with increased odds of ADHD and altered brain connectivity between the frontoparietal and default mode networks to sensorimotor cortices” (2). A 2018 study found that prenatal acetaminophen exposure was associated with an increased risk for lower IQ in addition to ASC and ADHD and recommended against the indiscriminate use of the OTC pain reliever (4). An increased risk was positively associated with the length of time acetaminophen was used during pregnancy (4). The recent studies cited here do not represent all of the research available on the topic. The 2021 consensus statement reports there are 29 observational studies in 14 cohorts including 220,000 mother-child pairs in which 26 have linked prenatal acetaminophen exposure to a wide array of adverse neurodevelopmental outcomes not limited to ADHD, ASC, and low IQ (3). Other neurodevelopmental disorders positively associated with acetaminophen exposure during pregnancy include decreased executive function, conduct disorder, language delays, cerebral palsy, and oppositional–defiant disorder (3). The potential for adverse fetal effects with acetaminophen use during pregnancy also includes the risk of urogenital and reproductive disorders.
Acetaminophen is an endocrine disruptor that is known to cross both the blood-brain barrier and placenta (3). Three are many studies showing reproductive toxicity and harm in both male and female offspring in mothers who use this OTC medication during pregnancy. Five out of 11 observational studies in six cohorts have suggested a link between acetaminophen exposure and urogenital and reproductive abnormalities (3). Studies have shown other urogenital and reproductive risks associated with acetaminophen use during pregnancy related to the reduction of sex hormone action in males and disruption of ovarian development in females (3). A 2018 study found that taking acetaminophen during pregnancy may reduce the future fertility of female offspring (9). A second 2018 study found that acetaminophen use depletes sulfated sex hormones across all populations (6). “The effect of taking acetaminophen on sulfated sex hormones was roughly equivalent to the effect of 35 years of aging” (6). A 2015 study was the first to demonstrate the effect of acetaminophen exposure on testosterone production and adds to existing evidence of the risks of acetaminophen use during pregnancy. Researchers found that using acetaminophen for one week or longer may increase the risk of reproductive disorders in male babies via suppression of testosterone production (10). Other research suggests risks that may be linked to acetaminophen use during pregnancy include sperm abnormalities, reduced anogenital distance (AGD) in boys, undescended testicles, and early female puberty (3;10). A 2018 study indicated both acetaminophen and Ibuprofen reduced the numbers of cells that develop into sperm and eggs called germ cells in human fetal cells and rats (7). The researchers said their results "raise concerns about the use of painkillers during pregnancy, as they could cause the unborn child to have fertility problems" (7). There are many studies showing the various adverse risks associated with prenatal acetaminophen exposure. Many researchers feel that research into alternative pain management strategies that are safe for use during pregnancy would be beneficial.
While the research on the safety of natural alternatives during pregnancy and breastfeeding is sparse, there are many remedies that are safe and effective that can be utilized depending on symptoms. Some herbs and supplements are indeed unsafe to use during pregnancy and or breastfeeding. Staying hydrated can help to prevent many symptoms that led individuals to use acetaminophen. I personally used arnica as my go-to homeopathic pain remedy during pregnancy and breastfeeding, but many others may be effective. Please check with a trusted provider prior to taking anything you think may be unsafe for use during pregnancy or breastfeeding.
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References
1.) Alemany, S., Avella-García, C., Liew, Z. 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. https://doi.org/10.1007/s10654-021-00754-4
2.) Baker, B. H., Lugo-Candelas, C., Wu, H., Laue, H. E., Boivin A, Gillet V, Aw N, Rahman T, Lepage, J. F., Whittingstall, K., Bellenger, J. P., Posner, J, Takser, L., Baccarelli, A. A. (2020). Association of Prenatal Acetaminophen Exposure Measured in Meconium with Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity. JAMA Pediatrics. Nov 1;174(11):1073-1081. 10.1001/jamapediatrics.2020.3080.
3.) Bauer, A.Z., Swan, S.H., Kriebel, D, Liew, Z., Taylor, H. S., Bornehag, C-G., Andrade, A.M., Olsen, J., Jensen, R. H., Mitchell, R. T., Skakkebaek, N. E., Jégou B., & Kristensen, D. M. (2021). Paracetamol use during pregnancy — a call for precautionary action. Nat Rev Endocrinol. https://doi.org/10.1038/s41574-021-00553-7
4.) Bauer, A.Z., Kriebel, D., Herbert, M.R., Bornehag, C.G., Swan, S.H.. (2018). Prenatal paracetamol exposure and child neurodevelopment: A review. Hormones and Behavior. May;101:125-147. 10.1016/j.yhbeh.2018.01.003.
5.) California Office of Environmental Health Hazard Assessment. (2019). Acetaminophen (paracetamol). https://oehha.ca.gov/proposition-65/chemicals/acetaminophen-paracetamol
6.) Cohen, I.V., Cirulli, E.T., Mitchell, M.W., Jonsson, T. J., Yu, J. Shah, N. Spector, T.D., Guo, L., Venter, J. C., Telenti, A. (2018). Acetaminophen (Paracetamol) Use Modifies the Sulfation of Sex Hormones. EBioMedicine by The Lancet. 28, 316- 323. https://doi.org/10.1016/j.ebiom.2018.01.033
7.) Hurtado-Gonzalez, P., Anderson, R. A., Macdonald, J., van den Driesche, S., Kilcoyne, K., Jørgensen, A., McKinnell, C., Macpherson, S., Sharpe, R. M., and Mitchell, R.T. (2018). Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems. Environmental Health Perspectives. 126, 4. https://doi.org/10.1289/EHP2307
8.) Ji, Y., Azuine, R.E., Zhang, Y., Hou, W., Hong, X., Wang, G., Riley, A., Pearson, C., Zuckerman, B., Wang, X. (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. 77(2):180–189. 10.1001/jamapsychiatry.2019.3259
9.) Society for Endocrinology. (2018). Taking paracetamol during pregnancy may reduce fertility of daughters. ScienceDaily. www.sciencedaily.com/releases/2018/01/180106103439.htm
10.) van den Driesche, S., Macdonald, J., Anderson, R. A., Johnston, Z. C., Chetty, T., Smith, L. B., Mckinell, C., Dean, A., Homer, N. Z., Jorgensen, A., Camacho-Moll, M. E., Sharpe, R. M., Mitchell, R. T. (2015). Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model. Science Translational Medicine. May, Vol. 7, Issue 288. 28810.1126/scitranslmed.aaa4097
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