To take or not to take: Acetaminophen during pregnancy

Emily, a 32-year-old pregnant female in her third trimester, visits your pharmacy to purchase acetaminophen to manage fever and myalgias related to an acute upper respiratory infection. She expresses concern about potential risks to her baby based on information she has seen in recent social media posts.You quickly check the resource you have on medication use in pregnancy, which indicates that “acetaminophen is the analgesic and antipyretic of first choice during pregnancy and can be used in any trimester when indicated.”1 However, you realize the material was published in 2015, which leaves you wondering if there has been a change to this recommendation.Acetaminophen is frequently the preferred over-the-counter (OTC) analgesic for managing pain and fever during pregnancy. Although it is generally viewed as safer than other OTC medications, such as nonsteroidal anti-inflammatory drugs (which can lead to pulmonary, cardiac and renal complications in the fetus) recent studies have raised concerns about the potential effects of acetaminophen on pregnancy outcomes and possible long-term neurological impacts on children.1-3SOGC statementAccording to a statement released by the Society of Obstetricians and Gynaecologists of Canada (SOGC) in 2021, acetaminophen has the best safety profile among OTC analgesics during pregnancy.2 The statement describes acetaminophen as a first-line treatment for fever and pain when medically indicated during pregnancy, emphasizing the importance of administering the lowest effective dose for the shortest duration necessary.2 Furthermore, the SOGC highlights the risks associated with untreated fever during pregnancy, which can include miscarriage, fetal organ malformations, cardiovascular complications and autism spectrum disorder.2 It also notes that untreated pain can lead to issues such as depression, anxiety and hypertension, all of which may negatively affect the pregnancy.2 Notably, the SOGC statement was published in 2021, and more recent literature has emerged. Reviewing the earlier data that informed the SOGC statement may provide valuable context for understanding the updated research.Earlier dataData published prior to 2021 on acetaminophen use in pregnancy includes a large case-control study of more than 16,110 infants, where 5,440 infants were exposed to acetaminophen during the first trimester.4 In this study, acetaminophen use did not appear to increase the risk of major birth defects, and acetaminophen use by women reporting a first-trimester infection and fever was associated with a decreased risk for certain malformations, such as anencephaly, cleft lip and gastroschisis.4 A literature review in 2009 concluded that available data did not indicate that acetaminophen is teratogenic in humans.5 Subsequent studies published in 2010–2012, indicated a possible association between acetaminophen exposure during the first or second trimester and cryptorchidism, although findings were not consistent in all populations.6-8Prenatal acetaminophen exposure has been linked to respiratory issues in children, with six studies from 1992–2011 suggesting a correlation with allergic rhinitis, wheezing or asthma.1 However, causation remains unproven, partly due to confounding factors, such as maternal illness and postnatal acetaminophen exposure.1,9 A Norwegian cohort study published in 2013 found associations between long-term (i.e., > 28 days) acetaminophen use during pregnancy and adverse neurodevelopmental outcomes in children, while a Danish cohort study published in 2014 linked acetaminophen exposure to hyperkinetic disorders and attention-deficit/hyperactivity disorder (ADHD)-like behaviours.10,11More recent dataTo add to the debate, three new studies related to prenatal acetaminophen use were published in 2024. A prospective cohort study suggested that increased prenatal acetaminophen use may be associated with poorer language development.12 In contrast, a Swedish sibling-controlled study found no significant difference in the incidence of neurodevelopmental disorders (i.e., autism, ADHD or intellectual disabilities) between children exposed to acetaminophen in utero and their unexposed siblings.13 Lastly, a prospective cohort study, based in Beijing, which included 501 patients reported that acetaminophen use, particularly in the first and second trimesters, may be associated with adverse pregnancy outcomes such as stillbirths and high birth weight.14Overall recommendationThe relationship between perinatal acetaminophen use and adverse pregnancy and infant outcomes remains uncertain. This uncertainty arises from the epidemiological data, which mainly rely on patient recall, may be affected by confounding factors, and are not consistent across studies.9,15 However, despite recent publications, the 2021 SOGC recommendation remains valid: pregnant women should only use acetaminophen when medically necessary, taking the smallest effective dose for the shortest duration.2 This recommendation aligns with a fundamental principle in prenatal care: minimizing drug exposure unless the benefits clearly outweigh the risks.Back to the patient case:Assess symptoms: Evaluate Emily’s presenting symptoms. Given that she is febrile, the benefits of pharmacologic treatment outweigh the possible risks.Educate on acetaminophen: As pharmacologic intervention is warranted, explain to Emily that acetaminophen is the first-line treatment for fever and pain in pregnancy and that its use in recommended doses is generally considered safe. Highlight that untreated fever and pain could have negative implications for her pregnancy.Discuss dosage and duration: Emphasize the importance of adhering to recommended doses and using acetaminophen only as needed.Address concerns: Acknowledge Emily’s worries about potential risks and discuss the evidence regarding acetaminophen. Provide reassurance that, while some studies suggest an association with behavioural issues, asthma and cryptorchidism, findings are not consistent, and causation has not been established.SummaryAcetaminophen remains a critical option for managing pain and fever during pregnancy, given its favourable safety profile compared to other analgesics. Pharmacists should continue to guide patients such as Emily, balancing the need for effective symptom management with the latest evidence regarding safety. By fostering open communication and providing evidence-based recommendations, pharmacists can play an essential role in supporting maternal health while alleviating concerns surrounding medication use during pregnancy.Katelyn Halpape is a clinical pharmacist at the Dube Centre for Mental Health in Saskatoon, SK, and an Assistant Professor in the College of Pharmacy and Nutrition at the University of Saskatchewan.References:Schaefer C, Peters PWJ, Miller RK. Drugs during pregnancy and lactation: treatment options and risk assessment. 3rd ed. London: Elsevier/Academic Press; 2014.Hutson JR, Smith GN, Codsi E, et al. Statement on the use of acetaminophen for analgesia and fever in pregnancy. Society of Obstetricians and Gynaecologists of Canada; November 8, 2021. (accessed October 22, 2024).FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy. September 2, 2019. (accessed October 22, 2024).Feldkamp ML, Meyer RE, Krikov S, et al. Acetaminophen use in pregnancy and risk of birth defects: findings From the National Birth Defects Prevention Study. Obstet Gynecol 2010;115(1):109.Scialli AR, Ang R, Breitmeyer J, et al. A review of the literature on the effects of acetaminophen on pregnancy outcome. Reprod Toxicol 2010;30(4):495-507.Jensen MS, Rebordosa C, Thulstrup AM, et al. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology 2010;21(6):779-85.Kristensen DM, Hass U, Lesné L, et al. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum Reprod 2011;26(1):235-44.Snijder CA, Kortenkamp A, Steegers EAP, et al. Intrauterine exposure to mild analgesics during pregnancy and the occurrence of cryptorchidism and hypospadia in the offspring: the Generation R Study. Hum Reprod 2012;27(4):1191-201.Henderson AJ, Shaheen SO. Acetaminophen and asthma. Paediatr Respir Rev 2013;14(1):9-16.Brandlistuen RE, Ystrom E, Nulman I, et al. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 2013;42(6):1702-13.Liew Z, Ritz B, Rebordosa C, et al. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr 2014;168(4):313-20.Woodbury ML, Cintora P, Ng S, et al. Examining the relationship of acetaminophen use during pregnancy with early language development in children. Pediatr Res 2024;95(7):1883-96.Ahlqvist VH, Sjöqvist H, Dalman C, et al. Acetaminophen use during pregnancy and children’s risk of autism, ADHD, and intellectual disability. JAMA 2024;331(14):1205-14.Xu M, Wang R, Du B, et al. Association of acetaminophen use with perinatal outcomes among pregnant women: a retrospective cohort study with propensity score matching. BMC Pregnancy Childbirth 2024;24(1):268.Horsager-Boehrer R. Acetaminophen is still safe in pregnancy, despite controversy. Your Pregnancy Matters. UT Southwestern Medical Center. (accessed October 16, 2024).